Article
Neonicotinoid insecticide exposures reported to six poison centers in Texas
Human and Experimental Toxicology 2014, Vol. 33(6) 568–573 ª The Author(s) 2014 Reprints and permission: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0960327114522500 het.sagepub.com
MB Forrester
Abstract Neonicotinoids are a relatively newer class of insecticide. Used primarily in agriculture, neonicotinoids are also used for flea control in domestic animals. Information on human exposures to neonicotinoids is limited. Neonicotinoid exposures reported to Texas poison centers during 2000–2012 were identified and the distribution by selected factors examined. Of 1,142 total exposures, most products contained imidacloprid (77%) or dinotefuran (17%). The exposures were seasonal with half reported during May–August. The most common routes of exposure were ingestion (51%), dermal (44%), and ocular (11%). The distribution by patient age was 5 years or less (28%), 6–19 years (9%), 20 years or more (61%), and unknown (2%); and 64% of the patients were female. Of all, 97% of the exposures were unintentional and 97% occurred at the patient’s own residence. The management site was on-site (92%), already at/en route to a health care facility (6%), and referred to a health care facility (2%). The medical outcomes included no effect (22%), minor effect (11%), moderate effect (1%), not followed judged nontoxic (14%), not followed minimal effects (46%), unable to follow potentially toxic (1%), and unrelated effect (4%). The most commonly reported adverse clinical effects were ocular irritation (6%), dermal irritation (5%), nausea (3%), vomiting (2%), oral irritation (2%), erythema (2%), and red eye (2%). The most frequently reported treatments were dilution/wash (85%) and food (6%). In summary, these data suggest that the majority of neonicotinoid exposures reported to the poison centers may be managed outside of health care facilities with few clinical effects expected. Keywords Neonicotinoid, insecticide, neonicotinoid insecticide, poison center
Introduction Chloronicotinyl neonicotinoid compounds are a comparatively new major class of insecticide, first marketed in the early 1990s, used for crop protection against piercing or soil insects and flea control on cats and dogs.1 They include acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. Neonicotinoids function as agonists at the postsynaptic nicotinergic acetylcholine receptors (nAChRs), causing acetylcholine excess (cholinergic syndrome). They are highly selective for the nAChRs in insects compared with mammals. Moreover, they have poor permeability of the blood–brain barrier. As a result, neonicotinoids are considered less likely to cause morbidity and mortality in humans. Neonicotinoids accounted for 11–15% of the worldwide insecticide market in 2004.2
Published information on potentially adverse human exposures to neonicotinoid insecticides is limited, often involving case reports or case series of occupational exposures or intentional self-harm.3–12 The clinical effects of adverse neonicotinoid exposure may resemble those of nicotine toxicity.3 The observed effects often are mild and include tachycardia, hypertension, hypotension, nausea, vomiting, headache, abdominal pain, diarrhea, dizziness, drowsiness,
Texas Department of State Health Services, Austin, TX, USA Corresponding author: MB Forrester, Texas Department of State Health Services, Environmental Epidemiology and Disease Registries Section, 1100 W 49th Street, Austin, Texas 78756, USA. Email: [email protected]
Forrester
muscle weakness, mydriasis, and fever. However, more serious adverse effects such as respiratory failure, sedation, seizures, and rhabdomyolysis have been reported.3–9 Deaths have occurred in association with neonicotinoid use.3,7,10–12 It has been suggested in the literature that some of the clinical effects may be due to the formulation ingredients in the products other than the neonicotinoid, although further detail was not provided. There is currently no antidote for neonicotinoid poisoning in mammals.2 Decontamination and symptomatic and supportive care may be used to treat such exposures.3,4,6,8 Poison centers are telephone consultation services that provide information on and assist in the management of potentially adverse exposures to a variety of substances, including insecticides. One study in the United Kingdom examined 105 neonicotinoid exposures reported to poison centers,5 while another described 70 such exposures reported to a poison center in Taiwan.3 Among their various findings, both studies suggested that neonicotinoid insecticide exposures might be less serious than exposures to other types of insecticide reported to poison centers.3,5 This investigation describes neonicotinoid exposures reported to a large poison center system in the United States. Examination of a large number of potentially adverse neonicotinoid insecticide exposures will add to the currently limited information on the topic and might clarify the circumstances under which such exposures might occur, the outcomes and clinical effects that might be expected, and how such exposures might be successfully managed. In order to reduce the number of such exposures, public health providers might use this information to educate individuals who might get exposed to neonicotinoid insecticides. In addition, health care providers might use the information to guide them in the management of neonicotinoid exposures that they might encounter.
Materials and methods This retrospective study used data collected by the Texas Poison Center Network (TPCN), a system of six poison centers that together service the entire state with a current population of over 25 million. The six poison centers use a single, common electronic database to collect demographic and clinical data on all calls in a consistent manner. The data fields and allowable data options are standardized by the American Association of Poison Control Centers
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(AAPCC). A given patient might be reported to the TPCN multiple times, possibly through more than one poison center. The TPCN has a procedure for identifying and combining multiple records for the same patient. Cases were all neonicotinoid insecticide exposures reported to the TPCN during 2000–2012. In the TPCN database, every substance involved in an exposure is assigned a seven-digit PoisIndex code provided by MicromedexTM (Truven Health Analytics, Ann Arbor, Michigan, USA). Usually, each PoisIndex code is assigned to a specific substance or product. PoisIndex codes for related substances are grouped in a single, seven-digit Generic code. For example, there is a single Generic code for pyrethroid only insecticides, all of which are assigned a different PoisIndex code. Unfortunately, there is no Generic code specific to neonicotinoid insecticides. Thus, an Internet search was performed to identify the names of products containing neonicotinoids. The TPCN database then was searched to identify exposures to any of these products as well as to any of the seven specific neonicotinoids. Each neonicotinoid product might be expected to be assigned its own PoisIndex code. However, during the course of this investigation, it was discovered that one of these PoisIndex codes could be used for any neonicotinoid. Moreover, it was found that another PoisIndex code could be used for both a neonicotinoid product and another product that did not contain a neonicotinoid. The records of all exposures assigned these two PoisIndex codes were reviewed to determine whether they appeared to involve a neonicotinoid and, if so, which neonicotinoid. Exposures involving substances in addition to the neonicotinoid insecticide and those not followed to a final medical outcome were included in the study. The distribution of exposures was determined for active ingredients, year of call, month of call, patient age and gender, exposure route, exposure site, urbanization status, management site, medical outcome, and most commonly reported adverse clinical effects and treatments. In order to examine urbanization status, each of the 254 Texas counties was designated as rural or urban based on US Office of Management and Budget definitions of metropolitan and nonmetropolitan. The exposures were grouped into those originating from rural counties and urban counties and the rate was calculated for the two groups based on the 2000 Census. The medical outcome or severity of an exposure is assigned by the poison center staff and is based on the observed or anticipated adverse clinical effects. Medical outcome is classified according to the following
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Table 1. Active ingredients in neonicotinoid insecticide exposures reported to the Texas Poison Center Network during 2000–2012. Active ingredients Imidacloprid Dinotefuran Nitenpyram Imidacloprid þ moxidectin Imidacloprid þ beta-cyfluthrin Dinotefuran þ permethrin and pyriproxyfen Imidacloprid þ cyfluthrin Dinotefuran þ pyriproxyfen Imidacloprid þ tau-fluvalinate and tebuconazole Imidacloprid þ muscalure Acetamiprid Thiamethoxam Clothianidin Unknown neonicotinoid Total
Number
%
775 150 58 33 23 23
67.9 13.1 5.1 2.9 2.0 2.0
21 20 15
1.8 1.8 1.3
7 6 6 3 2 1142
0.6 0.5 0.5 0.3 0.2
criteria: no effect (no symptoms due to exposure), minor effect (some minimally troublesome symptoms), moderate effect (more pronounced and prolonged symptoms), major effect (symptoms that are life-threatening or cause significant disability or disfigurement), and death. Sometimes exposures are not followed to a final medical outcome because of resource constraints or the inability to obtain subsequent information on the patient. In these instances, the poison center staff record the expected outcome of the exposure. These expected outcomes are grouped into the following categories: not followed but judged as nontoxic exposure (symptoms not expected), not followed but minimal symptoms possible (no more than minor symptoms possible), and unable to follow but judged as a potentially toxic exposure. Another medical outcome category is unrelated effect where the exposure was probably not responsible for the symptoms. The adverse clinical effects and treatments are recorded in the TPCN database by selecting from a number of check boxes for specific adverse clinical effects (n ¼ 131) and treatments (n ¼ 68). Adverse clinical effects and treatments also may be recorded in the record notes; however, this is not always done, and the recording is not done in a consistent manner. Thus, detailed information on adverse clinical effects and treatments beyond its reported presence is not available.
In order to evaluate whether neonicotinoid insecticide exposures reported to the TPCN might be less serious than exposures to other types of insecticide, the proportion of exposures that were known or expected to result in serious medical outcomes (moderate effect, major effect, death, and unable to follow but judged as a potentially toxic exposure) was calculated for neonicotinoid exposures as well as exposures to two other groups of insecticide: carbamate/chlorinated hydrocarbon/organophosphate and pyrethroid/ pyrethrin. Carbamate, chlorinated hydrocarbon, and organophosphate insecticides were not examined separately because a number of products included combinations of these types of insecticide. The same applied to pyrethroid and pyrethrin insecticides. For this analysis, cases where the medical outcome was designated as an unrelated effect and where the exposure was probably not responsible for the symptoms were excluded—n ¼ 47 neonicotinoids, n ¼ 1,012 carbamate/chlorinated hydrocarbon/organophosphates, and n ¼ 1,513 pyrethroid/pyrethrins. The serious outcome rates for the three groups were evaluated for statistical significance by calculating the ratio of the rate for neonicotinoids to the rate for the other insecticides (rate ratio, RR) and 95% confidence interval (CI) by the Newcombe–Wilson method without continuity correction. The RRs were considered statistically significant if the 95% CI excluded 1.00. p values were not calculated. The Texas Department of State Health Services institutional review board considers this analysis exempt from ethical review.
Results There were 1,142 neonicotinoid insecticide exposures identified for this investigation. Table 1 shows the distribution by active ingredients in the product. The most common neonicotinoid was imidacloprid (alone or in combination with other substances—moxidectin, beta-cyfluthrin, cyfluthrin, tau-fluvalinate and tebuconazole, and muscalure) reported in 874 (76.5%) of the exposures, followed by dinotefuran (alone or in combination with other substances—permethrin and pyriproxyfen) reported in 193 (16.9%) exposures. The mean annual number of neonicotinoid exposures (rounded to a whole number) was 52 in 2000–2003, 94 in 2004–2007, and 112 in 2008–2012. There was a seasonal trend with 296 (25.9%) of the exposures reported during January–April (mid-winter to mid-spring), 568 (49.7%) reported during May–August (mid-spring to
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Table 2. Serious medical outcome rate for neonicotinoid and other insecticides reported to the Texas Poison Center Network during 2000–2012. Totala Serious outcomeb Serious rate (%)
Insecticide
Neonicotinoid 1095 Carbamate/chlorinated hydrocarbon/organophosphate 11,841 Pyrethroid/pyrethrin 23,752
32 1389 1680
2.9 11.7 7.1
RR
95% CI
– – 0.25 0.18–0.35 0.41 0.29–0.58
Note: RR ¼ rate ratio, ratio of neonicotinoid serious outcome rate to rate of other insecticide; CI ¼ confidence interval. If the 95% CI excludes 1.00, then it is considered to be statistically significant. a Total cases excluding those with a medical outcome of unrelated effect. b Moderate effect, major effect, death, and unable to follow but judged as a potentially toxic exposure.
Table 3. Most common adverse clinical effects of neonicotinoid insecticide exposures reported to the Texas Poison Center Network during 2000–2012. Total exposures Adverse clinical effect Ocular irritation or pain Dermal irritation or pain Nausea Vomiting Oral irritation Red eye Erythema Rash Numbness Dizziness Total
Serious exposures
Number
%
Number
%
74 61 32 27 25 20 20 17 14 13 1142
6.5 5.3 2.8 2.4 2.2 1.8 1.8 1.5 1.2 1.1
6 2 5 2 1 3 3 3 1 2 32
18.8 6.3 15.6 6.3 3.1 9.4 9.4 9.4 3.1 6.3
mid-summer), and 278 (24.3%) reported during September–December (mid-summer to mid-winter). The age distribution was 318 (27.8%) 5 years or less, 98 (8.6%) 6–19 years, 701 (61.4%) 20 years or more, and 25 (2.2%) unknown age. The patient was female in 735 (64.4%) cases, male in 404 (35.4%), and unknown gender in 3 (0.3%). The exposure involved ingestion of the insecticide in 580 (50.8%) of the cases, dermal contact in 501 (43.9%), ocular exposure in 128 (11.2%), inhalation in 41 (3.6%), injection in 10 (0.9%), otic exposure in 2 (0.2%), unspecified other in 3 (0.3%), and unknown in 4 (0.4%). A given exposure might involve more than one route, so the sum of the individual routes will be greater than the total number of cases. The rate per 1,000,000 population was 46.4 for rural counties and 54.4 for urban counties. The exposure occurred at the patient’s own residence in 1,107 (96.9%) of the cases. The circumstances of the exposure were 1,104 (96.7%) unintentional, 19 (1.7%)
intentional (16 misuse, 1 suspected attempted suicide, and 2 unknown), 17 (1.5%) adverse reaction, and 2 (0.2%) other (malicious intent). Most (1,053 or 92.2%) of the patients were managed on-site (nonhealth care facility), while 66 (5.8%) were already at or en route to a health care facility when the poison center was contacted, 21 (1.8%) were referred to a health care facility by the poison center, and 2 (0.2%) were managed at an unspecified or unknown site. The distribution by medical outcome was 246 (21.5%) no effect, 126 (11.0%) minor effect, 16 (1.4%) moderate effect, 0 (0.0%) major effect, 0 (0.0%) death, 162 (14.2%) not followed but judged as nontoxic exposure, 529 (46.3%) not followed but minimal symptoms possible, 16 (1.4%) unable to follow but judged as a potentially toxic exposure, and 47 (4.1%) unrelated effect. Table 2 compares the serious medical outcome rate of neonicotinoid insecticides to two other groups of insecticides. Although a small proportion of exposures were serious for all three groups, the serious outcome rates were significantly lower for neonicotinoid insecticides than for carbamate/chlorinated hydrocarbon/organophosphate and pyrethroid/pyrethrin insecticides. Table 3 presents the most frequently reported adverse clinical effects. Reported cardiovascular effects were chest pain (2, 0.2%), hypertension (2, 0.2%), and tachycardia (2, 0.2%). No instances of seizures or rhabdomyolysis were reported. The most commonly recorded treatments were decontaminated by dilution or wash (970, 84.9%), administration of food (63, 5.5%), administration of antihistamines (17, 1.5%), and decontamination by fresh air (12, 1.1%). Other reported treatments were administration of steroids (9), antibiotics (7), IV fluids (2), oxygen (2), and bronchodilators (1) and decontamination by activated charcoal (2), and unspecified emetic (1). No treatment was reported for 123 (10.8%) of the exposures.
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Discussion This study describes neonicotinoid insecticide exposures reported to a large poison center system. Although serious outcomes and even deaths have been reported with exposures to these pesticides, there is limited information on human exposures to neonicotinoids, much of it consisting of case reports and case series.3–12 The most commonly reported neonicotinoid was imidacloprid, followed by dinotefuran. The other two investigations using poison center data likewise found imidacloprid to be the most commonly reported neonicotinoid. However, the UK and Taiwan studies found nitenpyram and acetamiprid to be the next most commonly reported neonicotinoids, respectively.3,5 This might indicate that the particular neonicotinoids reported to poison centers might depend on the country and perhaps even smaller geographic areas. If the particular neonicotinoids differ in toxicity, then poison centers and other health care providers might need to consider the particular neonicotinoid when managing an exposure. In this study, the serious outcome rate was 3.1% for imidacloprid alone, 0.7% for dinotefuran alone, and 0.0% for nitenpyram alone, suggesting that there are differences in the toxicity of the different neonicotinoids. The annual number of exposures doubled during the 13-year study period. The Taiwan investigation using poison center data likewise observed an annual increase in reported exposures.3 There was a seasonal pattern with half of the exposures reported during the mid-spring to mid-summer months. This might be expected with more intensive crop-growing activity occurring and pets more likely to be let outdoors during the spring and summer; thus, more insecticides might be expected to be used. The majority of patients were adult and most were female. In the UK study, the patients were almost evenly divided between adults and children as well as gender,5 while the Taiwan study observed the majority of patients to be male.3 The differences in patient demographics between the present and the UK and Taiwan investigations may reflect differences in the study criteria, operations of the poison centers, or the types of exposures that are reported to them. For example, the UK study involved only unintentional exposures while the present study and the Taiwan study included unintentional and intentional exposures. The most commonly reported route was by ingestion, followed by dermal contact, ocular, and inhalation. In
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the UK and Taiwan investigations using poison center data, the most frequent exposure route was ingestion.3,5 The reported exposure rate was higher in urban counties than in rural counties. This might be unexpected, considering that one of the primary uses of neonicotinoid insecticides is for crop protection against piercing or soil insects.1 However, such insecticides might have been used to protect plants in patients’ home gardens. Moreover, neonicotinoid insecticides also are used for flea control on cats and dogs.1 In addition, the preponderance of the exposures in this study was reported to have occurred at the patient’s own residence. The majority of exposures were unintentional, with less than 2% intentional (and only one of these was a suspected attempted suicide). This is in contrast to the UK study, where all of the exposures were unintentional,5 and the Taiwan study, where 69% were due to attempted suicide.3 Again, the observed differences may be due to the differences in study criteria, poison center operations, or the types of exposures that are reported. Only 32 (2.9%) of the neonicotinoid exposures resulted in serious outcomes, and no major outcomes or deaths were reported. Moreover, the serious outcome rate for neonicotinoid insecticides was substantially lower than that for carbamate/chlorinated hydrocarbon/organophosphate and pyrethroid/pyrethrin insecticides. This is consistent with the other two poison center investigations. The UK study found neonicotinoids to have less serious medical outcomes than pyrethroids and carbamates.5 In the Taiwan investigation, the mortality rate for neonicotinoids was lower than that for organophosphates and carbamates but similar to that for pyrethrins and pyrethroids.3 The preponderance (92%) of the neonicotinoid exposures in the present study was not managed at a health care facility. This is not surprising, considering that 97% of the exposures did not result in serious outcomes; if poison center staff do not consider an exposure to be serious, they are less likely to refer it to a health care facility. The specific adverse clinical effects were reported in only a fraction of the exposures. The most commonly reported effects were ocular, dermal, gastrointestinal, and neurological in nature and tended to be consistent with those observed in the literature.3–9 The most frequent treatments were some form of decontamination or symptomatic or supportive care. The literature described similar treatment of neonicotinoid exposures.3,4,6,8 There are limitations to this investigation. Reporting of potentially adverse exposures to neonicotinoid
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insecticides to the TPCN is not mandatory. Thus, all such exposures are not likely to have been reported, and those that were reported may not be representative of all exposures. Moreover, there might be differences in the tendency to report exposures to neonicotinoids and other insecticides; that is, exposures to some insecticides might be more likely to be reported than others. This might affect the comparison of serious outcome rates between neonicotinoids and the two other insecticide groups. In addition, as outlined in methods’ section, it was difficult to identify neonicotinoid exposures. As a result, some exposures might have been missed and not included in this study, and some exposures might have been included that were not actually involve neonicotinoids, although the author reviewed the substances documented for all of the cases in an effort to minimize this. Furthermore, a given patient may have been reported to the TPCN more than once. Although the TPCN have a procedure in place for identifying and combining multiple records that were created for the same patient, multiple records might be missed. As a result, the same patient might be counted multiple times in an analysis. Also, some of the clinical effects may be due to the ingredients other than the neonicotinoid in the products. In conclusion, neonicotinoid exposures reported to poison centers may be increasing. The majority of neonicotinoid exposures reported to the poison centers may be managed outside of health care facilities with few clinical effects expected. Neonicotinoid insecticides appear to tend to result in less serious outcomes than other major types of insecticide. Conflict of interest The authors declared no conflicts of interest.
Funding This work was supported by a public health emergency preparedness grant (2U90TP617001-11) from the Centers for Disease Control and Prevention.
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References 1. Vale JA. Poisoning due to neonicotinoid insecticides. Clin Toxicol 2008; 46: 404–405. 2. Tomizawa M and Casida JE. Neonicotinoid insecticide toxicology: mechanisms of selective action. Annu Rev Pharmacol Toxicol 2005; 45: 247–268. 3. Phua DH, Lin CC, Wu ML, et al. Neonicotinoid insecticides: an emerging cause of acute pesticide poisoning. Clin Toxicol 2009; 47: 336–341. 4. Lin PC, Lin HJ, Liao YY, et al. Acute poisoning with neonicotinoid insecticides: a case report and literature review. Basic Clin Pharmacol Toxicol 2013; 112: 282–286. 5. Adams RD, Perry L, Bennett A, et al. The NPIS pesticide surveillance project neonicotinoids: comparison of toxicity against other insecticide classes. Clin Toxicol 2013; 51: 353. 6. Imamura T, Yanagawa Y, Nishikawa K, et al. Two cases of acute poisoning with acetamiprid in humans. Clin Toxicol 2010; 48: 851–853. 7. Iyyadurai R, George IA and Peter JV. Imidacloprid poisoning newer insecticide and fatal toxicity. J Med Toxicol 2010; 6: 77–78. 8. Mohamed F, Gawarammana I, Robertson TA, et al. Acute human self poisoning with imidacloprid compound: a neonicotinoid insecticide. PLoS One 2009; 4: e5127. 9. Wu IW, Lin JL and Cheng ET. Acute poisoning with the neonicotinoid insecticide imidacloprid in N-methyl pyrrolidone. J Toxicol Clin Toxicol 2001; 39: 617–621. 10. Shadnia S and Moghaddam HH. Fatal intoxication with imidacloprid insecticide. Am J Emerg Med 2008; 26: 634.e1–634.e4. 11. David D, George IA and Peter JV. Toxicology of the newer neonicotinoid insecticides: imidacloprid poisoning in a human. Clin Toxicol 2007; 45: 485–486. 12. Proenca P, Teixeira H, Castanheira F, et al. Two fatal intoxication cases with imidacloprid: LC/MS analysis. Forensic Sci Int 2005; 153: 75–80.
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Neonicotinoid insecticide exposures reported to six poison centers in Texas
Human and Experimental Toxicology 2014, Vol. 33(6) 568–573 ª The Author(s) 2014 Reprints and permission: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0960327114522500 het.sagepub.com
MB Forrester
Abstract Neonicotinoids are a relatively newer class of insecticide. Used primarily in agriculture, neonicotinoids are also used for flea control in domestic animals. Information on human exposures to neonicotinoids is limited. Neonicotinoid exposures reported to Texas poison centers during 2000–2012 were identified and the distribution by selected factors examined. Of 1,142 total exposures, most products contained imidacloprid (77%) or dinotefuran (17%). The exposures were seasonal with half reported during May–August. The most common routes of exposure were ingestion (51%), dermal (44%), and ocular (11%). The distribution by patient age was 5 years or less (28%), 6–19 years (9%), 20 years or more (61%), and unknown (2%); and 64% of the patients were female. Of all, 97% of the exposures were unintentional and 97% occurred at the patient’s own residence. The management site was on-site (92%), already at/en route to a health care facility (6%), and referred to a health care facility (2%). The medical outcomes included no effect (22%), minor effect (11%), moderate effect (1%), not followed judged nontoxic (14%), not followed minimal effects (46%), unable to follow potentially toxic (1%), and unrelated effect (4%). The most commonly reported adverse clinical effects were ocular irritation (6%), dermal irritation (5%), nausea (3%), vomiting (2%), oral irritation (2%), erythema (2%), and red eye (2%). The most frequently reported treatments were dilution/wash (85%) and food (6%). In summary, these data suggest that the majority of neonicotinoid exposures reported to the poison centers may be managed outside of health care facilities with few clinical effects expected. Keywords Neonicotinoid, insecticide, neonicotinoid insecticide, poison center
Introduction Chloronicotinyl neonicotinoid compounds are a comparatively new major class of insecticide, first marketed in the early 1990s, used for crop protection against piercing or soil insects and flea control on cats and dogs.1 They include acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. Neonicotinoids function as agonists at the postsynaptic nicotinergic acetylcholine receptors (nAChRs), causing acetylcholine excess (cholinergic syndrome). They are highly selective for the nAChRs in insects compared with mammals. Moreover, they have poor permeability of the blood–brain barrier. As a result, neonicotinoids are considered less likely to cause morbidity and mortality in humans. Neonicotinoids accounted for 11–15% of the worldwide insecticide market in 2004.2
Published information on potentially adverse human exposures to neonicotinoid insecticides is limited, often involving case reports or case series of occupational exposures or intentional self-harm.3–12 The clinical effects of adverse neonicotinoid exposure may resemble those of nicotine toxicity.3 The observed effects often are mild and include tachycardia, hypertension, hypotension, nausea, vomiting, headache, abdominal pain, diarrhea, dizziness, drowsiness,
Texas Department of State Health Services, Austin, TX, USA Corresponding author: MB Forrester, Texas Department of State Health Services, Environmental Epidemiology and Disease Registries Section, 1100 W 49th Street, Austin, Texas 78756, USA. Email: [email protected]
Forrester
muscle weakness, mydriasis, and fever. However, more serious adverse effects such as respiratory failure, sedation, seizures, and rhabdomyolysis have been reported.3–9 Deaths have occurred in association with neonicotinoid use.3,7,10–12 It has been suggested in the literature that some of the clinical effects may be due to the formulation ingredients in the products other than the neonicotinoid, although further detail was not provided. There is currently no antidote for neonicotinoid poisoning in mammals.2 Decontamination and symptomatic and supportive care may be used to treat such exposures.3,4,6,8 Poison centers are telephone consultation services that provide information on and assist in the management of potentially adverse exposures to a variety of substances, including insecticides. One study in the United Kingdom examined 105 neonicotinoid exposures reported to poison centers,5 while another described 70 such exposures reported to a poison center in Taiwan.3 Among their various findings, both studies suggested that neonicotinoid insecticide exposures might be less serious than exposures to other types of insecticide reported to poison centers.3,5 This investigation describes neonicotinoid exposures reported to a large poison center system in the United States. Examination of a large number of potentially adverse neonicotinoid insecticide exposures will add to the currently limited information on the topic and might clarify the circumstances under which such exposures might occur, the outcomes and clinical effects that might be expected, and how such exposures might be successfully managed. In order to reduce the number of such exposures, public health providers might use this information to educate individuals who might get exposed to neonicotinoid insecticides. In addition, health care providers might use the information to guide them in the management of neonicotinoid exposures that they might encounter.
Materials and methods This retrospective study used data collected by the Texas Poison Center Network (TPCN), a system of six poison centers that together service the entire state with a current population of over 25 million. The six poison centers use a single, common electronic database to collect demographic and clinical data on all calls in a consistent manner. The data fields and allowable data options are standardized by the American Association of Poison Control Centers
569
(AAPCC). A given patient might be reported to the TPCN multiple times, possibly through more than one poison center. The TPCN has a procedure for identifying and combining multiple records for the same patient. Cases were all neonicotinoid insecticide exposures reported to the TPCN during 2000–2012. In the TPCN database, every substance involved in an exposure is assigned a seven-digit PoisIndex code provided by MicromedexTM (Truven Health Analytics, Ann Arbor, Michigan, USA). Usually, each PoisIndex code is assigned to a specific substance or product. PoisIndex codes for related substances are grouped in a single, seven-digit Generic code. For example, there is a single Generic code for pyrethroid only insecticides, all of which are assigned a different PoisIndex code. Unfortunately, there is no Generic code specific to neonicotinoid insecticides. Thus, an Internet search was performed to identify the names of products containing neonicotinoids. The TPCN database then was searched to identify exposures to any of these products as well as to any of the seven specific neonicotinoids. Each neonicotinoid product might be expected to be assigned its own PoisIndex code. However, during the course of this investigation, it was discovered that one of these PoisIndex codes could be used for any neonicotinoid. Moreover, it was found that another PoisIndex code could be used for both a neonicotinoid product and another product that did not contain a neonicotinoid. The records of all exposures assigned these two PoisIndex codes were reviewed to determine whether they appeared to involve a neonicotinoid and, if so, which neonicotinoid. Exposures involving substances in addition to the neonicotinoid insecticide and those not followed to a final medical outcome were included in the study. The distribution of exposures was determined for active ingredients, year of call, month of call, patient age and gender, exposure route, exposure site, urbanization status, management site, medical outcome, and most commonly reported adverse clinical effects and treatments. In order to examine urbanization status, each of the 254 Texas counties was designated as rural or urban based on US Office of Management and Budget definitions of metropolitan and nonmetropolitan. The exposures were grouped into those originating from rural counties and urban counties and the rate was calculated for the two groups based on the 2000 Census. The medical outcome or severity of an exposure is assigned by the poison center staff and is based on the observed or anticipated adverse clinical effects. Medical outcome is classified according to the following
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Table 1. Active ingredients in neonicotinoid insecticide exposures reported to the Texas Poison Center Network during 2000–2012. Active ingredients Imidacloprid Dinotefuran Nitenpyram Imidacloprid þ moxidectin Imidacloprid þ beta-cyfluthrin Dinotefuran þ permethrin and pyriproxyfen Imidacloprid þ cyfluthrin Dinotefuran þ pyriproxyfen Imidacloprid þ tau-fluvalinate and tebuconazole Imidacloprid þ muscalure Acetamiprid Thiamethoxam Clothianidin Unknown neonicotinoid Total
Number
%
775 150 58 33 23 23
67.9 13.1 5.1 2.9 2.0 2.0
21 20 15
1.8 1.8 1.3
7 6 6 3 2 1142
0.6 0.5 0.5 0.3 0.2
criteria: no effect (no symptoms due to exposure), minor effect (some minimally troublesome symptoms), moderate effect (more pronounced and prolonged symptoms), major effect (symptoms that are life-threatening or cause significant disability or disfigurement), and death. Sometimes exposures are not followed to a final medical outcome because of resource constraints or the inability to obtain subsequent information on the patient. In these instances, the poison center staff record the expected outcome of the exposure. These expected outcomes are grouped into the following categories: not followed but judged as nontoxic exposure (symptoms not expected), not followed but minimal symptoms possible (no more than minor symptoms possible), and unable to follow but judged as a potentially toxic exposure. Another medical outcome category is unrelated effect where the exposure was probably not responsible for the symptoms. The adverse clinical effects and treatments are recorded in the TPCN database by selecting from a number of check boxes for specific adverse clinical effects (n ¼ 131) and treatments (n ¼ 68). Adverse clinical effects and treatments also may be recorded in the record notes; however, this is not always done, and the recording is not done in a consistent manner. Thus, detailed information on adverse clinical effects and treatments beyond its reported presence is not available.
In order to evaluate whether neonicotinoid insecticide exposures reported to the TPCN might be less serious than exposures to other types of insecticide, the proportion of exposures that were known or expected to result in serious medical outcomes (moderate effect, major effect, death, and unable to follow but judged as a potentially toxic exposure) was calculated for neonicotinoid exposures as well as exposures to two other groups of insecticide: carbamate/chlorinated hydrocarbon/organophosphate and pyrethroid/ pyrethrin. Carbamate, chlorinated hydrocarbon, and organophosphate insecticides were not examined separately because a number of products included combinations of these types of insecticide. The same applied to pyrethroid and pyrethrin insecticides. For this analysis, cases where the medical outcome was designated as an unrelated effect and where the exposure was probably not responsible for the symptoms were excluded—n ¼ 47 neonicotinoids, n ¼ 1,012 carbamate/chlorinated hydrocarbon/organophosphates, and n ¼ 1,513 pyrethroid/pyrethrins. The serious outcome rates for the three groups were evaluated for statistical significance by calculating the ratio of the rate for neonicotinoids to the rate for the other insecticides (rate ratio, RR) and 95% confidence interval (CI) by the Newcombe–Wilson method without continuity correction. The RRs were considered statistically significant if the 95% CI excluded 1.00. p values were not calculated. The Texas Department of State Health Services institutional review board considers this analysis exempt from ethical review.
Results There were 1,142 neonicotinoid insecticide exposures identified for this investigation. Table 1 shows the distribution by active ingredients in the product. The most common neonicotinoid was imidacloprid (alone or in combination with other substances—moxidectin, beta-cyfluthrin, cyfluthrin, tau-fluvalinate and tebuconazole, and muscalure) reported in 874 (76.5%) of the exposures, followed by dinotefuran (alone or in combination with other substances—permethrin and pyriproxyfen) reported in 193 (16.9%) exposures. The mean annual number of neonicotinoid exposures (rounded to a whole number) was 52 in 2000–2003, 94 in 2004–2007, and 112 in 2008–2012. There was a seasonal trend with 296 (25.9%) of the exposures reported during January–April (mid-winter to mid-spring), 568 (49.7%) reported during May–August (mid-spring to
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Table 2. Serious medical outcome rate for neonicotinoid and other insecticides reported to the Texas Poison Center Network during 2000–2012. Totala Serious outcomeb Serious rate (%)
Insecticide
Neonicotinoid 1095 Carbamate/chlorinated hydrocarbon/organophosphate 11,841 Pyrethroid/pyrethrin 23,752
32 1389 1680
2.9 11.7 7.1
RR
95% CI
– – 0.25 0.18–0.35 0.41 0.29–0.58
Note: RR ¼ rate ratio, ratio of neonicotinoid serious outcome rate to rate of other insecticide; CI ¼ confidence interval. If the 95% CI excludes 1.00, then it is considered to be statistically significant. a Total cases excluding those with a medical outcome of unrelated effect. b Moderate effect, major effect, death, and unable to follow but judged as a potentially toxic exposure.
Table 3. Most common adverse clinical effects of neonicotinoid insecticide exposures reported to the Texas Poison Center Network during 2000–2012. Total exposures Adverse clinical effect Ocular irritation or pain Dermal irritation or pain Nausea Vomiting Oral irritation Red eye Erythema Rash Numbness Dizziness Total
Serious exposures
Number
%
Number
%
74 61 32 27 25 20 20 17 14 13 1142
6.5 5.3 2.8 2.4 2.2 1.8 1.8 1.5 1.2 1.1
6 2 5 2 1 3 3 3 1 2 32
18.8 6.3 15.6 6.3 3.1 9.4 9.4 9.4 3.1 6.3
mid-summer), and 278 (24.3%) reported during September–December (mid-summer to mid-winter). The age distribution was 318 (27.8%) 5 years or less, 98 (8.6%) 6–19 years, 701 (61.4%) 20 years or more, and 25 (2.2%) unknown age. The patient was female in 735 (64.4%) cases, male in 404 (35.4%), and unknown gender in 3 (0.3%). The exposure involved ingestion of the insecticide in 580 (50.8%) of the cases, dermal contact in 501 (43.9%), ocular exposure in 128 (11.2%), inhalation in 41 (3.6%), injection in 10 (0.9%), otic exposure in 2 (0.2%), unspecified other in 3 (0.3%), and unknown in 4 (0.4%). A given exposure might involve more than one route, so the sum of the individual routes will be greater than the total number of cases. The rate per 1,000,000 population was 46.4 for rural counties and 54.4 for urban counties. The exposure occurred at the patient’s own residence in 1,107 (96.9%) of the cases. The circumstances of the exposure were 1,104 (96.7%) unintentional, 19 (1.7%)
intentional (16 misuse, 1 suspected attempted suicide, and 2 unknown), 17 (1.5%) adverse reaction, and 2 (0.2%) other (malicious intent). Most (1,053 or 92.2%) of the patients were managed on-site (nonhealth care facility), while 66 (5.8%) were already at or en route to a health care facility when the poison center was contacted, 21 (1.8%) were referred to a health care facility by the poison center, and 2 (0.2%) were managed at an unspecified or unknown site. The distribution by medical outcome was 246 (21.5%) no effect, 126 (11.0%) minor effect, 16 (1.4%) moderate effect, 0 (0.0%) major effect, 0 (0.0%) death, 162 (14.2%) not followed but judged as nontoxic exposure, 529 (46.3%) not followed but minimal symptoms possible, 16 (1.4%) unable to follow but judged as a potentially toxic exposure, and 47 (4.1%) unrelated effect. Table 2 compares the serious medical outcome rate of neonicotinoid insecticides to two other groups of insecticides. Although a small proportion of exposures were serious for all three groups, the serious outcome rates were significantly lower for neonicotinoid insecticides than for carbamate/chlorinated hydrocarbon/organophosphate and pyrethroid/pyrethrin insecticides. Table 3 presents the most frequently reported adverse clinical effects. Reported cardiovascular effects were chest pain (2, 0.2%), hypertension (2, 0.2%), and tachycardia (2, 0.2%). No instances of seizures or rhabdomyolysis were reported. The most commonly recorded treatments were decontaminated by dilution or wash (970, 84.9%), administration of food (63, 5.5%), administration of antihistamines (17, 1.5%), and decontamination by fresh air (12, 1.1%). Other reported treatments were administration of steroids (9), antibiotics (7), IV fluids (2), oxygen (2), and bronchodilators (1) and decontamination by activated charcoal (2), and unspecified emetic (1). No treatment was reported for 123 (10.8%) of the exposures.
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Discussion This study describes neonicotinoid insecticide exposures reported to a large poison center system. Although serious outcomes and even deaths have been reported with exposures to these pesticides, there is limited information on human exposures to neonicotinoids, much of it consisting of case reports and case series.3–12 The most commonly reported neonicotinoid was imidacloprid, followed by dinotefuran. The other two investigations using poison center data likewise found imidacloprid to be the most commonly reported neonicotinoid. However, the UK and Taiwan studies found nitenpyram and acetamiprid to be the next most commonly reported neonicotinoids, respectively.3,5 This might indicate that the particular neonicotinoids reported to poison centers might depend on the country and perhaps even smaller geographic areas. If the particular neonicotinoids differ in toxicity, then poison centers and other health care providers might need to consider the particular neonicotinoid when managing an exposure. In this study, the serious outcome rate was 3.1% for imidacloprid alone, 0.7% for dinotefuran alone, and 0.0% for nitenpyram alone, suggesting that there are differences in the toxicity of the different neonicotinoids. The annual number of exposures doubled during the 13-year study period. The Taiwan investigation using poison center data likewise observed an annual increase in reported exposures.3 There was a seasonal pattern with half of the exposures reported during the mid-spring to mid-summer months. This might be expected with more intensive crop-growing activity occurring and pets more likely to be let outdoors during the spring and summer; thus, more insecticides might be expected to be used. The majority of patients were adult and most were female. In the UK study, the patients were almost evenly divided between adults and children as well as gender,5 while the Taiwan study observed the majority of patients to be male.3 The differences in patient demographics between the present and the UK and Taiwan investigations may reflect differences in the study criteria, operations of the poison centers, or the types of exposures that are reported to them. For example, the UK study involved only unintentional exposures while the present study and the Taiwan study included unintentional and intentional exposures. The most commonly reported route was by ingestion, followed by dermal contact, ocular, and inhalation. In
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the UK and Taiwan investigations using poison center data, the most frequent exposure route was ingestion.3,5 The reported exposure rate was higher in urban counties than in rural counties. This might be unexpected, considering that one of the primary uses of neonicotinoid insecticides is for crop protection against piercing or soil insects.1 However, such insecticides might have been used to protect plants in patients’ home gardens. Moreover, neonicotinoid insecticides also are used for flea control on cats and dogs.1 In addition, the preponderance of the exposures in this study was reported to have occurred at the patient’s own residence. The majority of exposures were unintentional, with less than 2% intentional (and only one of these was a suspected attempted suicide). This is in contrast to the UK study, where all of the exposures were unintentional,5 and the Taiwan study, where 69% were due to attempted suicide.3 Again, the observed differences may be due to the differences in study criteria, poison center operations, or the types of exposures that are reported. Only 32 (2.9%) of the neonicotinoid exposures resulted in serious outcomes, and no major outcomes or deaths were reported. Moreover, the serious outcome rate for neonicotinoid insecticides was substantially lower than that for carbamate/chlorinated hydrocarbon/organophosphate and pyrethroid/pyrethrin insecticides. This is consistent with the other two poison center investigations. The UK study found neonicotinoids to have less serious medical outcomes than pyrethroids and carbamates.5 In the Taiwan investigation, the mortality rate for neonicotinoids was lower than that for organophosphates and carbamates but similar to that for pyrethrins and pyrethroids.3 The preponderance (92%) of the neonicotinoid exposures in the present study was not managed at a health care facility. This is not surprising, considering that 97% of the exposures did not result in serious outcomes; if poison center staff do not consider an exposure to be serious, they are less likely to refer it to a health care facility. The specific adverse clinical effects were reported in only a fraction of the exposures. The most commonly reported effects were ocular, dermal, gastrointestinal, and neurological in nature and tended to be consistent with those observed in the literature.3–9 The most frequent treatments were some form of decontamination or symptomatic or supportive care. The literature described similar treatment of neonicotinoid exposures.3,4,6,8 There are limitations to this investigation. Reporting of potentially adverse exposures to neonicotinoid
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insecticides to the TPCN is not mandatory. Thus, all such exposures are not likely to have been reported, and those that were reported may not be representative of all exposures. Moreover, there might be differences in the tendency to report exposures to neonicotinoids and other insecticides; that is, exposures to some insecticides might be more likely to be reported than others. This might affect the comparison of serious outcome rates between neonicotinoids and the two other insecticide groups. In addition, as outlined in methods’ section, it was difficult to identify neonicotinoid exposures. As a result, some exposures might have been missed and not included in this study, and some exposures might have been included that were not actually involve neonicotinoids, although the author reviewed the substances documented for all of the cases in an effort to minimize this. Furthermore, a given patient may have been reported to the TPCN more than once. Although the TPCN have a procedure in place for identifying and combining multiple records that were created for the same patient, multiple records might be missed. As a result, the same patient might be counted multiple times in an analysis. Also, some of the clinical effects may be due to the ingredients other than the neonicotinoid in the products. In conclusion, neonicotinoid exposures reported to poison centers may be increasing. The majority of neonicotinoid exposures reported to the poison centers may be managed outside of health care facilities with few clinical effects expected. Neonicotinoid insecticides appear to tend to result in less serious outcomes than other major types of insecticide. Conflict of interest The authors declared no conflicts of interest.
Funding This work was supported by a public health emergency preparedness grant (2U90TP617001-11) from the Centers for Disease Control and Prevention.
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