Human poisoning with spinosad and flonicamid insecticides

Abstract

This report describes the first known case in the literature of acute exposure to a mixture of spinosad and flonicamid that resulted in a substantial clinical toxicities. An 80-year-old depressed female attempted suicide by drinking a mixture of 80-mL Conserve (Dow AgroSciences, Taipei, Taiwan) and 2–3 gram powder of flonicamid (Ishihara Sangyo Kaisha, Taipei, Taiwan). Spinosad was the main compound ingested. The clinical manifestations were mostly neurological, i.e. consciousness disturbance, shock, respiratory failure, pneumonitis and urinary retention. Endoscopic examination found grade 2a corrosive esophageal injury. After resuscitation, detoxification procedures and intensive care, the patient recovered fully without leaving any chronic sequels. An emerging question arising from this report is, why are the clinical symptoms so severe, given that both compounds were claimed safe in laboratory animals? The answer is unclear. One possible explanation is, the amount of spinosad ingested was far beyond the physiological safety dose that can be handled by human body. Other potential contributors to the clinical toxicities in this patient are the solvent compositions that were found in the Conserve insecticide formulation.

Introduction

According to the 26th Annual Report of the American Association of Poison Control Centers' National Poison Data System, substances involved most frequently in all human exposures in the USA were analgesics (13.3%), with insecticides poisoning being less common (3.8%). ¹ However, unintentional or intentional ingestion of insecticides/herbicides^2,3 is common in Taiwan because of easy access. Agriculture is an important industry in Taiwan. Workers and their families always have free access to insecticides/herbicides at their places of work and homes and this increases the risk of human exposure.

Spinosad ⁴ is a new insect control agent that is derived from a naturally occurring soil bacterium and is effective on several classes of insects, especially Lepidoptera larvae. Spinosad consists mainly of a mixture of spinosyns A and D and is registered for uses on a variety of crops in Taiwan. Spinosad has shown a significantly favorable improvement in its safety profile and therapeutic indices for mammals and other animals when compared with other traditional insecticides.^5–7 Flonicamid, another new insecticide, is a pyridinecarboxamide compound. ⁸ Research has shown that flonicamid has a unique mode of action and does not affect the target sites associated with any of the other known insecticide classes. ⁸ Flonicamid has incorrectly been classified as a neonicotinoid compound based solely on structural similarities. ⁹ Nevertheless, flonicamid differs chemically from the neonicotinoid and laboratory research has also shown that flonicamid does not affect the nicotinic acetylcholine receptor site. Flonicamid also has a low environmental impact and poses no risk to agricultural workers because of the low mammalian toxicity.

Conserve (Dow AgroSciences, Taipei, Taiwan) and flonicamid (Ishihara Sangyo Kaisha, Taipei, Taiwan) are new and popular insecticides in Taiwan due to excellent performance for pest control and good toxicological, environmental and ecotoxicological profiles. Conserve is available as 11.6% spinosyn A and D, 2% poloxemer, 2% ammonium naphthalene sulfonate, 1% silicone antifoam, 0.2% proxel GXL preservative, 4% propylene glycol, 0.15% xanthan gum, 0.9% smectite clays and 78.15% water. Flonicamid (N-cyanomethyl-4-trifluoromethylnicotinamide) is available as 10% water dispersible granule.

We are unaware of any reported human case of spinosad or flonicamid poisoning, since a search of the literature found only toxicological information obtained through animal studies laboratory.^6,7 However, a recent suicide attempt involving a mixture of spinosad and flonicamid insecticides has led us to review the clinical toxicity of these insecticides in human beings.

Case

An 80-year-old depressed female attempted suicide by drinking of a mixture 80 mL Conserve (Dow AgroSciences, Taipei, Taiwan) and 2–3 gram powder of flonicamid (Ishihara Sangyo Kaisha, Taipei, Taiwan). She was discovered by her family in 3 hours and sent immediately to our hospital. On arrival, she was unconscious (G1M1V1), in shock (blood pressure 70/50 mmHg, pulse rate 81/minute) and breathing irregularly (respiratory rate 20/minute). The patient was rapidly intubated, followed by gastric lavage with large amounts of normal saline, and infusion of 1 g/kg activated charcoal and 250 mL magnesium citrate via a nasogastric tube. Fluid challenge and dopamine infusion were also administered. Blood tests showed leukocytosis with left shift (white blood cell count 11,500/μL, neutrophils 74%). Metabolic acidosis with respiratory compensation (post-intubation: pH 7.413, pCO₂ 23.4 mmHg, pO₂ 310.6 mmHg, HCO₃ 14.6 mm/L and SaO₂ 99.9%) was also noted. Chest radiography showed hazy infiltration in both the lungs. The resuscitation was successful with rapid correction of shock, regain of consciousness and successful extubation in couple of days. General malaise, multiple oral ulcerations, pneumonitis and urinary retention were found after extubation. Endoscopy showed grade 2a corrosive esophageal injury. Electroencephalography revealed diffuse slow waves over bilateral hemisphere with intermittent diffuse theta wave, 6–7 Hz, 30–40 μV, which was compatible with diffuse cortical dysfunction. Screening spirometry showed a characteristic pattern of restrictive lung disease, with forced vital capacity (FVC): 0.79 L (31.10%), forced expiratory volume in one second (FEV1): 0.79 L (40.91%) and FEV1/FVC: 100%. Urodynamic study showed detrusor hyperactivity with impaired contractility with incomplete relaxing sphincter, normal urethral closing pressure, for which neurogenic bladder was considered. The following hospitalization course had been uneventful and she was discharged after 5 weeks without leaving any chronic sequels.

Discussion

This is the first known case in the literature of acute oral exposure to a mixture of 80 mL of 11.6% spinosad and 2–3 gram flonicamid that resulted in substantial clinical toxicities. By volume, it seemed that spinosad was the main compound ingested. The clinical manifestations were mostly neurological, i.e. consciousness disturbance, shock, respiratory failure, pneumonitis and urinary retention. Endoscopic examination found grade 2a corrosive esophageal injury. After resuscitation, detoxification procedures and intensive care, the patient recovered fully without leaving any chronic sequels.

The spinosyns have a unique mode of action involving disruption of nicotinic acetylcholine receptors. ⁵ Initial investigations suggested that the primary action of spinosyn A affected the insect nervous system and disrupted neuronal activity by exciting motor neurons and causing involuntary muscle contractions, eventually leading to paralysis and death.^10,11 Further studies found that spinosyn interacted with both gamma-aminobutyric acid receptors and nicotinic acetylcholine receptors, thereby implicating these receptors in the mode of action. ¹² Subsequent investigations provided additional evidence for such a unique mode of action, involving an unidentified subtype of nicotinic acid receptors as well as an antagonistic effect on γ-aminobutyric acid receptors. ⁴ Most recently, knockout studies in Drosophila melanogaster implicated the Da6 subunit of the nicotinic acetylcholine receptor as a target site of spinosyn. ¹³ Therefore, spinosad has been classified as nicotinic acetylcholine receptor allosteric activator (group 5), ¹⁴ for which there is strong evidence that action at one or more of this class of protein is responsible for insecticidal effect.

On the other hand, flonicamid is another systemic insecticide with selective activity against homoptera, acting as feeding inhibitor with high mortality due to starvation. ⁸ Flonicamid has been classified as selective homopteran feeding blocker (group 9c), ¹⁴ for which target protein responsible for biological activity is unknown, or uncharacterized.

An emerging question arising from this report is, why are the clinical symptoms so severe, given that both compounds were claimed relatively safe in laboratory animals?^6,7 According to Reasor’s laboratory,^6,7 the no observed effect level (NOEL) for the 13-week study was 0.005% (6 mg/kg/day) spinosad, and for the 18-month study was 0.008% (11 mg/kg/day) spinosad for male and female CD-1 mice. ⁶ In rats, the NOEL in the 13-week studies was 0.012% (24 mg/kg/day) spinosad. ⁷ The NOEL at 2 years was 0.005% (2.4 mg/kg/day) spinosad. ⁷ The answer is unclear. One possible explanation is the amount of spinosad ingested was far beyond the physiologic safety dose that can be handled by human body.

Finally, other potential contributors to the clinical toxicities in this patient are the solvent compositions, for example 2% poloxemer surfactant, 2% ammonium naphthalene sulfonate surfactant, 1% silicone antifoam, 0.2% proxel GXL preservative, 4% propylene glycol, 0.15% xanthan gum and 0.9% smectite clays that found in the Conserve insecticide formulation. Liquid silicone is an inert material that is utilized for cosmetic procedures by physicians as well as illegally by non-medical personnel. A case of acute pneumonitis following intramammary injections of a proprietary silicone fluid mixture has been described in 1994. ¹⁵ This seems to be a serious, potentially life-threatening illness and the pathogenesis has not yet been well established. The compound 1,2-benzisothiazolin-3-one is the active ingredient in proxel GXL, a commonly used preservative in many industries. Allergic contact dermatitis to 1,2-benzisothiazolin-3-one in the carpet industry has been identified. ¹⁶ Propylene glycol is a diluent found in many intravenous and oral drugs, including phenytoin, diazepam and lorazepam. Propylene glycol is eliminated from the body by oxidation through alcohol dehydrogenase to form lactic acid. Under normal conditions, the body converts lactate to pyruvate and metabolizes pyruvate through the Krebs cycle. Lactic acidosis^17,18 has occurred in patients, often those with renal dysfunction, who were receiving prolonged infusions of drugs that contain propylene glycol as a diluent.