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Case Report

A Rare Case of Suicide by Ingestion of Phorate: A Case Report and a Review of the Literature

by
Angelo Montana
1,*,
Venerando Rapisarda
2,
Massimiliano Esposito
1,*,
Francesco Amico
1,
Giuseppe Cocimano
1,
Nunzio Di Nunno
3,
Caterina Ledda
2 and
Monica Salerno
1
1
Legal Medicine, Department of Medical, Surgical and Advanced Technologies, “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy
2
Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
3
Department of History, Society and Studies on Humanity, University of Salento, 73100 Lecce, Italy
*
Authors to whom correspondence should be addressed.
Healthcare 2021, 9(2), 131; https://doi.org/10.3390/healthcare9020131
Submission received: 5 January 2021 / Revised: 23 January 2021 / Accepted: 26 January 2021 / Published: 29 January 2021
(This article belongs to the Special Issue Forensic Science and Legal Medicine: A Multidisciplinary Puzzle!)
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Abstract

:
Phorate is a systemic organophosphorus pesticide (OP) that acts by inhibiting cholinesterases. Recent studies have reported that long-term low/moderate exposure to OP could be correlated with impaired cardiovascular and pulmonary function and other neurological effects. A 70-year-old farmer died after an intention ingestion of a granular powder mixed with water. He was employed on a farm for over 50 years producing fruit and vegetables, and for about 20 years, he had also applied pesticides. In the last 15 years, he used phorate predominantly. The Phorate concentration detected in gastric contents was 3.29 µg/mL. Chronic exposure to phorate is experimentally studied by histopathological changes observed in the kidney. In the light of current literature, our case confirms that there is an association between renal damage and chronic exposure to phorate in a subject exposed for years to the pesticide. Autopsies and toxicological analyses play a key role in the reconstruction of the dynamics, including the cause of the death.

1. Introduction

Phorate (IUPAC name: O,O-diethyl S-[(ethylsulfanyl)methyl] phosphorodithioate; CAS Number: 298-02-2) is a systemic organophosphorus pesticide (OP) that acts by inhibiting cholinesterases, which are the enzymes involved in transmitting nerve impulses [1]. Phorate is highly toxic to birds, fish, and mammals (male rat oral LD50 for the metabolite phorate oxon = 0.88 mg/kg) [2], and accidental human exposure, resulting in death in some instances, has been reported [3].
The self-poisoning of organophosphorus pesticide is a major clinical and public health problem across many rural regions. Some studies have highlighted higher suicide rates among farmers than the general population [4,5,6]. Some reviews pointed out higher suicide rates among farmers than any other occupational group in the United Kingdom and in Australia [7,8,9]. In contrast, applicators in Italy had a lower rate of accidents and suicide [10]. In fact, Parrón et al. [11] showed a suicide rate in certain areas of Spain where there was greater use of phorate [12], and ecological and case studies suggested an association between organophosphate pesticide (OP) use and suicide [13].
The Agricultural Health Study (AHS) is a large, prospective cohort study of private pesticide applicators (mostly farmers), designed to study associations between cancer and other chronic diseases and farm-related exposures [14]. Pesticides are associated with the following cancer: lung cancer [15,16], pancreatic cancer [17], colon and rectal cancer [18,19] all lymphohematopoietic cancers [20] leukemia [21], Non-Hodgkin lymphoma [22], multiple myeloma [23], bladder cancer [24] brain cancer and melanoma [25,26].
In humans, chronic exposure to phorate has been shown to cause a reduced acetylcholinesterase (AChE) activity in both blood plasma and the brain [27]. Its mechanism of action consists in the inhibition of AChE activity by phosphorylating the serine hydroxyl group of the substrate-binding domain [28]. In cases where there is an accumulation of acetylcholine (ACh), the “cholinergic syndrome” can develop, which causes an overstimulation of nicotinic, muscarinic, and central ACh receptors; at the level of the central nervous system (CNS), this causes different effects such as headache, drowsiness, dizziness, confusion, blurred vision, slurred speech, ataxia, coma, and convulsions, until there is a block of the respiratory center [29,30,31]. Recent studies have highlighted that long-term low/moderate exposure to OP could be correlated with impaired neurobehavioral function or other neurological effects [32,33], while the studies have reported higher suicide rates among farmers who used it than in the general population [34,35]. Other investigations on the chronic toxicity of OP have shown kidney damage in animal models mediated by several mechanisms such as damage to the cell membrane and proteins through oxidative stress induced by the generation of free oxygen radicals, functional disturbances related to plasma membrane injury, cellular DNA damage, and activation of apoptosis-related p53 [35,36,37,38,39,40,41,42,43]. In the present study, we report a case of suicide carried out through the high ingestion of phorate of an agricultural worker exposed to phorate, at low doses, for several years. However, there is no evidence for an association between nephrotoxicity and chronic long-term exposure to low levels of phorate exposure in humans in the literature. Through this case report and a systematic review of animal and human models, this study aims to correlate kidney damage with chronic exposure to pesticide and phorate in the subjects exposed for years to the pesticide and dead after an intentional ingestion of phorate.

2. Materials and Methods

2.1. Case Description

A 70-year-old farmer was found disoriented and sweaty by his daughter. The man had been drinking a granular powder mixed with water. She immediately alerted the emergency services, but the man suddenly collapsed during transport to the emergency department. Despite resuscitation maneuvers, he died. He had been a farmer for over 50 years producing fruit and vegetables, and for about 20 years, he had used phorate. In the last nine years, he had used predominantly phorate twice/month, for 6–7 working h/day from March to July. From his medical records, compiled by his family doctor, it appears that the worker had had a history of depression for 10 years that had been treated pharmacologically with a specialist prescription.
No ethical committee was required. Written informed consent was obtained from the relatives.

2.2. Autopsy Findings

A complete autopsy was performed 48 h after death. External examination of the body showed a robust physique (height 165 cm, weight 81 kg), with hypostasis on the upper half of the body (head, neck, superior thorax, and upper limbs). The autopsy revealed the heart with a regular shape, weight 470 g, and measured 12 × 9.5 × 6.8 cm; the coronary arteries were healthy with a right dominance. The myocardium and the valvular apparatus were normal. The analysis of the respiratory system was performed through the removal of the heart-lung block. The larynx was edematous; the lung parenchyma appeared increased in volume, heavy (left 430 g, right lung 500 g), the consistency was emphysematous during palpation with congestion and petechiae. The esophagus walls had a brownish coloration; the stomach contained 100 mL of brown liquid, which was sampled (see Figure 1a). Organs taken during the autopsy showed evident signs of diffused visceral congestion. The organ specimens were fixed in 10% buffered formalin and embedded in paraffin. Microscopy with hematoxylin-eosin staining was performed: the brain showed intraparenchymal haemorrhages, perineuronal and perivasal oedema. The lungs displayed subpleural and endoalveolar haemorrhages, massive endoalveolar edema, and scattered bronchopneumonia outbreaks; there was an infiltrate of peribronchiolar lymphocytes and neutrophils were detected in the lungs and laryngeal mucosa.
Specimens of biological fluids (blood, urine, and gastric contents) taken during the autopsy were frozen (−20 °C). Sections of tissue were set up with hematoxylin and eosin for histological examination.

2.3. Poisoning

To determine what the subject had ingested, gastric contents were collected at the time of autopsy and stored at −20 °C, and 1 mL of samples was analyzed, after liquid/liquid extraction, by gas chromatography–mass spectrometry (GC–MS) analysis (single quadrupole).

2.4. Chronic Exposure Assessment

In the absence of chronic pre-mortem exposure data, the subject’s kidney sections, after H&E staining, were observed to detect the presence of damage due to chronic exposure to phorate to verify if there had been an extended exposure during life.

2.5. Systematic Review

In accordance with the PRISMA statement a systematic review was performed [16].

2.6. Literature Search

SCOPUS, Medline (using PubMed as the search engine), Embase, and Web of Sciences databases were searched up to 30 September 2020 for the association of toxic phorate exposure with suicide and histopathological kidney changes in humans as the primary outcome.
MeSH was used with the following entry terms: “Phorate” AND “death”; “Phorate” AND “suicide”; “Phorate” AND “kidney”. A search of the identified manuscripts was then made for inclusion suitability in this systematic review, and the research papers of significance were collected and reviewed.

2.7. Inclusion and Exclusion Criteria

The following criteria were used: (1) Studies that evaluated the correlation between Phorate and death (suicide, kidney damage, animals and humans). The following exclusion criteria were then used: (2) animal studies, (3) original articles in non-English language; and (4) editorials, posters, abstracts.
For duplicate studies, the article with detailed information was included.

2.8. Quality Assessment and Data Extraction

Two reviewers, A.M. and C.L. processed articles independently. The title, abstract, and full text of each potentially pertinent study was reviewed. Through the consultation and debate of additional reviewer V.R., any divergence on the eligibility of the studies was determined. The following information was extracted and organized from all suitable papers: authors, year of publication, the nationality of subjects, and study characteristics.

2.9. Characteristics of Eligible Studies

After a search of the scientific literature by reviewers, a total of 15 documents were collected.
Two were excluded after a subsequent review of the title and abstract, and 5 studies were ruled out after a review of the manuscript. In conclusion, 8 studies satisfied totally the inclusion criteria and were included in the systematic review. A flowchart depicting the choice of studies is shown in Figure 2.
A summary of the details of the included research papers is reported in Table 1.

2.10. Outcomes of Eligible Studies

From the eight studies, only two were carried out on humans; both were case reports of acute exposure.
Peter et al. [44] reported a case of a 30-year-old woman who, after a family dispute, swallowed 50 mL of phorate. She survived after gastric lavage. Khatiwada et al. [3] reported a case of a 30-year-old woman and her 80-year-old grandmother who unintentionally ingested phorate granules mistaken for food (sesame seeds). The 30-year-old woman was pronounced dead on arrival at the emergency department; the 80-year-old woman survived after resuscitation procedures.
The other six studies were conducted on animals and related chronic exposure to phorate. The experiments were conducted on rats that were given only phorate or with other pesticides for a period from a minimum of 14 days to a maximum of 24 weeks consecutively. Due to chronic exposure, these rats showed kidney and DNA damage.

3. Results

In our case, phorate concentration detected in the gastric contents was 3.29 µg/mL (see Figure 1b).
According to the macroscopic and microscopic findings, the cause of death was attributed to respiratory failure with pulmonary dysfunction due to an acute cholinergic crisis. The larynx was edematous; the lung parenchyma appeared increased in volume, and the consistency was emphysematous during palpation. The esophagus walls had a brownish coloration; the stomach contained 100 mL of brown liquid, which was sampled. Histological examination of the lungs revealed a generalized stasis; it was observed that inside the lungs, the alveolar spaces were occupied by an eosinophilic proteinaceous material and some hemosiderin-laden macrophages associated with passive congestion. The use of a higher power microscope allowed us to see intra-alveolar edema and alveolar capillaries’ engorgement.
The glomerulus exhibited hypercellularity (see Figure 3a). At certain places, leucocytic infiltration was noticed. There was a deposition of eosin-positive material between the tubules and degenerating tubules (see Figure 3b). A shrunken of the glomeruli were seen in some areas. Thus more spaces between Bowman’s capsule and the glomerulus were displayed (see Figure 3c). There was increased cellularity in the glomerulus (see Figure 3d), tightly filling Bowman’s capsule, and dilated tubules were seen with the separation of epithelial cells from the underlying basement membrane. The proximal and distal tubules showed hypertrophy of epithelial cells with obliterated lumina.

4. Discussion

In the case reported here, death followed fatal oral ingestion of phorate by a farmer who had used phorate for about 20 years. He had used predominantly phorate twice per month for 6–7 working h/day from March to July in the last nine years.
In the literature, there were never described fatal cases of accidental ingestion of phorate. It was described a case after unintentional ingestion of phorate by a 30-year-old woman in the literature. The woman confused phorate granules for sesame seeds, she mixed it with pickle and rice and consumed it. She was taken to the hospital and, after resuscitation, was transferred to the intensive care unit. She was extubated on the 17th day and discharged on the 23rd day [3].
In another case report a 28-year-old woman, in India, after quarrelling with her family, impulsively swallowed 50 mL of phorate. Immediately she lost consciousness and was taken to hospital arriving about nine hours after her suicide attempt. After five days of deep coma, the patient started to recover and was fully conscious by day 15 [44].
The reason behind the elevated risk of mood disorder in farming populations is unclear. The neurotoxic effects of high-level acute poisoning are well known and involve inhibition of the enzyme AChE, provoking changes in peripheral, autonomic, and CNS function resulting in a group of physical, cognitive, and psychiatric symptoms. Nevertheless, organophosphorus pesticide (OP) disrupts many other neurotransmitters, and some of these are entailed in mood regulation, such as serotonin. This could clarify the connection between pesticide exposure and mood disorders seen in earlier studies [39,40].
Compared to other occupational groups was reported that workers exposed to OP had a high incidence of depression and anxiety [32,33], but, to the best of our knowledge, our case is the first in which phorate was ingested intentionally.
Deaths from acute OP intoxication usually result from the depression of the CNS respiratory system and respiratory failure caused by a combination of bronchoconstriction and excessive respiratory secretions [41,42].
Chronic renal failure is one of the problems manifested in clinical follow-up of the patients and causes an increase in OP intoxication mortality [43]. In this specific case, after the exposition for several years to phorate, the patient developed depressive disorders, and the postmortem histological findings showed chronic kidney damage.
A significant number of studies demonstrated that phorate induces structural DNA modification with cellular damage in cultured human and animal cells [50,51]. The production of reactive oxygen species (ROS) in the vicinity of the protein molecule and the strong binding of phorate to the proteins induce the protein damage [52]. Several studies confirmed the ROS generating capability of phorate both extracellularly and intracellularly, with mitochondrial damage. In fact, the production of ROS induced mitochondrial damage, which suggests phorate toxicity in exposed cells [53,54]. Damage to lysosomal membranes is known to release lysosome protease into intracellular spaces, affecting neighboring cells, and triggers cell death due to necrosis [55].
These structural cell alterations have been highlighted in the kidney, a target organ of phorate as highlighted both in animal and human studies. In general acute renal failure is due to the oxidative stress, where OP directly damages renal tubules and renal parenchyma, and to the myoglobinuria caused by muscle fasciculation [56,57,58].
Chronic exposure to phorate is experimentally studied by histopathological changes observed in the proximal renal tubules; similar changes were observed in experiments conducted on animal and human models [33,34].
Qi et al. [46] investigated the protective effect of quercetin against the combined toxic action induced by the mixture of four organophosphate pesticides (dimethoate, acephate, dichlorvos, and phorate) given to the rats for 90 days, using metabonomics detected in rat urine. The authors showed the toxicity induced by chronic exposure to low-level mixture of OPs on the metabolism of fatty acids, energy and sex hormones, antioxidant defense system, DNA damage, and kidney function.
In a very similar study, Du et al. [46] in the plasma rats carried out a metabolomic analysis of the combined toxic action of long-term low-level exposure to a mixture of four organophosphate pesticides (dichlorvos, dimethoate, acephate, and Phorate) given for 24 weeks. The results highlighted that the mixture of OP pesticides induced oxidative stress, renal dysfunction, disturbed the metabolism of lipids and amino acids, and the thyroid gland. Observational histopathological changes in the kidney are marked by renal tubular epithelial cell swelling and granular degeneration, which were observed in the low-dose group 12 weeks after treatment.
Histopathological changes in the kidney were seen in the high- and middle-dose groups than those in the low-dose group 12 weeks after treatment. The main characteristic findings were the renal tubular epithelial cell swelling, granular degeneration, and vacuolar degeneration.
The same study was carried out by Sun et al. [47], analyzing the urine of rats investigating the toxic effect of long-term and low-level exposure to phorate using a metabolomics approach ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Male Wistar rats were administered low doses of 0.05, 0.15, or 0.45 mg/kg body weight (BW) phorate daily through water for 24 weeks consecutively. The levels of creatinine (CR) and urea nitrogen (BUN) were significantly elevated in the high-dose group, indicating kidney damage after exposure to phorate.
Li et al. [48] examined the effect of quercetin against a mixture of four organophosphates (dichlorvos, acephate, dimethoate, and phorate) inducing nephrotoxicity in rats, given for 90 days. Similar to the previous studies, the histopathological examination performed on the kidney sections (H&E method) showed extensive cell vacuolar denaturation and desquamation of the epithelial lining of the tubules, renal damage by impairing the reabsorption capacity of the proximal tubules, and by decreasing glomerular filtration rate.
Mohssen [49], in his study, evaluated biochemical (serum creatinine) and histopathological kidney alterations in male Swiss albino mice, Mus musculus, caused by subchronic inhalation of the recommended field dose of Phorate (20 kg/ha). In particular, from the second to twelfth week of exposure, the kidney, in the cortical tubules, showed at the beginning widespread cloudy degeneration, with a few foci of hydropic degeneration until the blockage of the lumen by necrotic cells. In the interstitial spaces, red blood cells and macrophages were present in the first weeks, with an increase of the chronic inflammatory infiltrate associated with foci of hemorrhage in the cortex. Kidney damage is caused by the ability of phorate to induce inflammation-inducing the formation of reactive oxygen, damage to the mitochondria, damage to the cell membrane and proteins, including enzymes, which finally result in loss of membrane fluidity and function. These alterations are associated with an early injury to cellular membranes after exposure to different toxins that induce plasma membrane injury disturbances.
Moreover, phorate exhibits cellular DNA damage and activation of apoptosis-related p53, caspase 3 and 9 genes, inducing the generation of intracellular ROS that induce reduced activities of the antioxidant enzymes catalase (CAT), glutathione (GSH) and lipid peroxidation (LPO), which were observed in the kidney of rats exposed to phorate [36]. Male Wistar rats exposed to phorate at varying oral doses of 0.046, 0.092, or 0.184 mg phorate/kg BW for 14 days showed, after histological investigations of tissues, changes in kidney function such as renal blood flow, concentrating substances, and biotransformation of the parent compounds make this tissue sensitive to a variety of toxins. The greater Bowman’s space showed with infiltration of renal parenchyma by inflammatory leukocytes, dilated blood vessels, and renal necrosis; similar results were shown by Mohssen [49].

5. Conclusions

Through this case and the data reported in the literature, the authors want to point out that: (a) the use of OP and phorate should be limited in time because increases symptoms of psychological distress, including suicidal thoughts; (b) the OP, particularly after the prolonged exposition, have a toxic effect on the kidney that is histologically notable; (c) in this case, the cause of death was attributed to respiratory failure with pulmonary dysfunction due to an acute cholinergic crisis; (d) phorate induces DNA structural alterations and cellular damage in cultured human cells and in animal cells determining qualitative changes in tissues in the kidney.
Moreover, since there are, to date, few reports of similar deaths, our report provides useful information regarding this particular kind of death. All aspects of the forensic death investigation triad -investigation (history), pathology, and laboratory results—are essential and must be evaluated in context with one another. In this regard, the toxicological investigation was decisive, allowing us to identify the stomach’s substance and was analyzed after liquid/liquid extraction by GC–MS analysis (single quadrupole).
Since extremely hazardous neurotoxic pesticides are still ordinally used in developing countries, further research on mental health is crucial to make an important preventive action by governmental and international bodies.

Author Contributions

Conceptualization, A.M. and C.L.; methodology, M.E., and V.R.; software, F.A. and N.D.N.; validation, N.D.N., A.M., and M.S.; formal analysis, C.L., V.R., and G.C.; investigation, G.C.; resources, AM., M.S. and C.L.; data curation, V.R., and N.D.N.; writing—original draft preparation, A.M. and C.L., writing—review and editing, A.M. and C.L.; supervision, V.R., and A.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

All procedures performed in the study were in accordance with the ethical standards of the institution and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent Statement

Informed consent was obtained from the relatives.

Data Availability Statement

All data are included in the main text.

Acknowledgments

The authors thank the Scientific Bureau of the University of Catania for language support.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. World Health Organization. Pesticide Residues in Food-2004: Evaluations 2004: Part II-Toxicological; WHO: Geneva, Switzerland, 2006; Volume 178. [Google Scholar]
  2. Snider, T.H.; McGarry, K.G.; Babin, M.C.; Jett, D.A.; Platoff, G.E., Jr.; Yeung, D.T. Acute toxicity of Phorate oxon by oral gavage in the Sprague-Dawley rat. Fundam. Toxicol. Sci. 2016, 3, 195–204. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Khatiwada, S.; Tripathi, M.; Pokharel, K.; Acharya, R.; Subedi, A. Ambiguous Phorate granules for sesame seeds linked to accidental organophosphate fatal poisoning. JNMA J. Nepal Med. Assoc. 2012, 52, 49–51. [Google Scholar] [CrossRef] [PubMed]
  4. Meltzer, H.; Griffiths, C.; Brock, A.; Rooney, C.; Jenkins, R. Patterns of suicide by occupation in England and Wales: 2001–2005. Br. J. Psychiatry 2008, 193, 73–76. [Google Scholar] [CrossRef] [PubMed]
  5. Miller, K.; Burns, C. Suicides on farms in South Australia, 1997–2001. Aust. J. Rural Health 2008, 16, 327–331. [Google Scholar] [CrossRef]
  6. Lee, W.J.; Alavanja, M.C.; Hoppin, J.A.; Rusiecki, J.A.; Kamel, F.; Blair, A.; Sandler, D.P. Mortality among pesticide applicators exposed to chlorpyrifos in the Agricultural Health Study. Environ. Health Perspect. 2007, 115, 528–534. [Google Scholar] [CrossRef]
  7. Gregoire, A. The mental health of farmers. Occup. Med. 2002, 52, 471–476. [Google Scholar] [CrossRef] [Green Version]
  8. MacFarlane, E.; Benke, G.; Del Monaco, A.; Sim, M.R. Cancer incidence and mortality in a historical cohort of Australian pest control workers. Occup. Environ. Med. 2009, 66, 818–823. [Google Scholar] [CrossRef] [PubMed]
  9. MacFarlane, E.; Benke, G.; Del Monaco, A.; Sim, M.R. Causes of death and incidence of cancer in a cohort of Australian pesticide-exposed workers. Ann. Epidemiol. 2010, 20, 273–280. [Google Scholar] [CrossRef] [PubMed]
  10. Torchio, P.; Lepore, A.R.; Corrao, G.; Comba, P.; Settimi, L.; Belli, S.; Magnani, C.; di Orio, F. Mortality study on a cohort of Italian licensed pesticide users. Sci. Total Environ. 1994, 149, 183–191. [Google Scholar] [CrossRef]
  11. Parrón, T.; Hernández, A.F.; Villanueva, E. Increased risk of suicide with exposure to pesticides in an intensive agricultural area. A 12-year retrospective study. Forensic Sci. Int. 1996, 79, 53–63. [Google Scholar] [CrossRef]
  12. Stallones, L. Suicide and potential occupational exposure to pesticides, Colorado, 1990–1999. J. Agromed. 2006, 11, 107–112. [Google Scholar] [CrossRef] [PubMed]
  13. London, L.; Flisher, A.J.; Wesseling, C.; Mergler, D.; Kromhout, H. Suicide and exposure to organophosphate insecticides: Cause or effect? Am. J. Ind. Med. 2005, 47, 308–321. [Google Scholar] [CrossRef] [PubMed]
  14. Alavanja, M.C.; Sandler, D.P.; McMaster, S.B.; Zahm, S.H.; McDonnell, C.J.; Lynch, C.F.; Blair, F.A. The Agricultural Health Study. Environ. Health Perspect. 1996, 104, 362–369. [Google Scholar] [CrossRef] [PubMed]
  15. Purdue, M.P.; Hoppin, J.A.; Blair, A.; Dosemeci, M.; Alavanja, M.C. Occupational exposure to organochlorine insecticides and cancer incidence in the Agricultural Health Study. Int. J. Cancer 2007, 120, 642–649. [Google Scholar] [CrossRef] [Green Version]
  16. Hou, L.; Lee, W.J.; Rusiecki, J.; Hoppin, J.A.; Blair, A.; Bonner, M.R.; Lubin, J.H.; Samanic, C.; Sandler, D.P.; Dosemeci, M.; et al. Pendimethalin exposure and cancer incidence among pesticide applicators. Epidemiology 2006, 17, 302. [Google Scholar] [CrossRef]
  17. Andreotti, G.; Freeman, L.E.B.; Hou, L.; Coble, J.; Rusiecki, J.; Hoppin, J.A.; Silverman, D.T.; Alavanja, M.C. Agricultural pesticide use and pancreatic cancer risk in the Agricultural Health Study cohort. Int. J. Cancer 2009, 124, 2495–2500. [Google Scholar] [CrossRef] [Green Version]
  18. Lee, W.J.; Sandler, D.P.; Blair, A.; Samanic, C.; Cross, A.J.; Alavanja, M.C.R. Pesticide use and colorectal cancer risk in the Agricultural Health Study. Int. J. Cancer 2007, 121, 339–346. [Google Scholar] [CrossRef] [Green Version]
  19. van Bemmel, D.M.; Visvanathan, K.; Beane Freeman, L.E.; Coble, J.; Hoppin, J.A.; Alavanja, M.C. S-ethyl-N, N-dipropylthiocarbamate exposure and cancer incidence among male pesticide applicators in the Agricultural Health Study: A prospective cohort. Environ. Health Perspect. 2008, 116, 1541–1546. [Google Scholar] [CrossRef] [Green Version]
  20. Rusiecki, J.A.; Patel, R.; Koutros, S.; Beane-Freeman, L.; Landgren, O.; Bonner, M.R.; Alavanja, M.C. Cancer incidence among pesticide applicators exposed to permethrin in the Agricultural Health Study. Environ. Health Perspect. 2009, 117, 581–586. [Google Scholar] [CrossRef]
  21. Bonner, M.R.; Coble, J.; Blair, A.; Beane Freeman, L.E.; Hoppin, J.A.; Sandler, D.P.; Alavanja, M.C. Malathion exposure and the incidence of cancer in the agricultural health study. Am. J. Epidemiol. 2007, 166, 1023–1034. [Google Scholar] [CrossRef] [Green Version]
  22. Kang, D.; Park, S.K.; Beane-Freeman, L.; Lynch, C.F.; Knott, C.E.; Sandler, D.P.; Hoppin, J.A.; Dosemeci, M.; Coble, J.; Lubin, J.; et al. Cancer incidence among pesticide applicators exposed to trifluralin in the Agricultural Health Study. Environ. Res. 2008, 107, 271–276. [Google Scholar] [CrossRef] [PubMed]
  23. Rajkumar, S.V. MGUS and smoldering multiple myeloma: Update on pathogenesis, natural history, and management. Hematology 2005, 2005, 340–345. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Koutros, S.; Lynch, C.F.; Ma, X.; Lee, W.J.; Hoppin, J.A.; Christensen, C.H.; Sandler, D.P. Heterocyclic aromatic amine pesticide use and human cancer risk: Results from the US Agricultural Health Study. Int. J. Cancer 2009, 124, 1206–1212. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Lee, W.J.; Blair, A.; Hoppin, J.A.; Lubin, J.H.; Rusiecki, J.A.; Sandler, D.P.; Dosemeci, M.; Alavanja, M.C.R. Cancer incidence among pesticide applicators exposed to chlorpyrifos in the Agricultural Health Study. J. Natl. Cancer Inst. 2004, 96, 1781–1791. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Mahajan, R.; Blair, A.; Coble, J.; Lynch, C.F.; Hoppin, J.A.; Sandler, D.P.; Alavanja, M.C. Carbaryl exposure and incident cancer in the Agricultural Health Study. Int. J. Cancer 2007, 121, 1799–1805. [Google Scholar] [CrossRef]
  27. Kashyap, S.K.; Jani, J.P.; Saiyed, H.N.; Gupta, S.K. Clinical effects and cholinesterase activity changes in workers exposed to Phorate (Thimet). J. Environ. Sci. Health B 1984, 19, 479–489. [Google Scholar] [CrossRef]
  28. Rapisarda, V.; Ledda, C.; Matera, S.; Fago, L.; Arrabito, G.; Falzone, L.; Marconi, A.; Libra, M.; Loreto, C. Absence of t (14; 18) chromosome translocation in agricultural workers after short-term exposure to pesticides. Mol. Med. Rep. 2017, 15, 3379–3382. [Google Scholar] [CrossRef] [Green Version]
  29. Casida, J.E.; Quistad, G.B. Organophosphate toxicology: Safety aspects of nonacetylcholinesterase secondary targets. Chem. Res. Toxicol. 2004, 17, 983–998. [Google Scholar] [CrossRef]
  30. Vinceti, M.; Filippini, T.; Violi, F.; Rothman, K.J.; Costanzini, S.; Malagoli, C.; Wise, L.A.; Odone, A.; Signorelli, C.; Iacuzio, L.; et al. Pesticide exposure assessed through agricultural crop proximity and risk of amyotrophic lateral sclerosis. Environ. Health 2017, 16, 91. [Google Scholar] [CrossRef]
  31. Costa, C.; Rapisarda, V.; Catania, S.; Di Nola, C.; Ledda, C.; Fenga, C. Cytokine patterns in greenhouse workers occupationally exposed to α-cypermethrin: An observational study. Environ. Toxicol. Pharmacol. 2013, 36, 796–800. [Google Scholar] [CrossRef]
  32. Farahat, T.M.; Abdelrasoul, G.M.; Amr, M.M.; Shebl, M.M.; Farahat, F.M.; Anger, W.K. Neurobehavioural effects among workers occupationally exposed to organophosphorous pesticides. Occup. Environ. Med. 2003, 60, 279–286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Kamel, F.; Hoppin, J.A. Association of pesticide exposure with neurologic dysfunction and disease. Environ. Health Perspect. 2004, 112, 950–958. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Martínez-Valenzuela, C.; Waliszewski, S.M.; Amador-Muñoz, O.; Meza, E.; Calderón-Segura, M.E.; Zenteno, E.; Huichapan-Martínez, J.; Caba, M.; Félix-Gastélum, R.; Longoria-Espinoza, R. Aerial pesticide application causes DNA damage in pilots from Sinaloa, Mexico. Environ. Sci. Pollut. Res. Int. 2017, 24, 2412–2420. [Google Scholar] [CrossRef] [PubMed]
  35. Numan, I.T.; Hassan, M.Q.; Stohs, S.J. Endrin-induced depletion of glutathione and inhibition of glutathione peroxidase activity in rats. Gen. Pharmacol. Vasc. Syst. 1990, 21, 625–628. [Google Scholar] [CrossRef]
  36. Bakheet, S.A.; Attia, S.M.; Al-Rasheed, N.M.; Al-Harbi, M.M.; Ashour, A.E.; Korashy, H.M.; Abd-Allah, A.R.; Saquib, Q.; Al-Khedhairy, A.A.; Musarrat, J. Salubrious effects of dexrazoxane against teniposide-induced DNA damage and programmed cell death in murine marrow cells. Mutagenesis 2011, 26, 533–543. [Google Scholar] [CrossRef] [Green Version]
  37. Mohanty, G.; Mohanty, J.; Nayak, A.K.; Mohanty, S.; Dutta, S.K. Application of comet assay in the study of DNA damage and recovery in rohu (Labeo rohita) fingerlings after an exposure to Phorate, an organophosphate pesticide. Ecotoxicology 2011, 20, 283–292. [Google Scholar] [CrossRef]
  38. Moher, D.; Shamseer, L.; Clarke, M.; Ghersi, D.; Liberati, A.; Petticrew, M.; Shekelle, P.; Stewart, L.A. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 2015, 4, 1. [Google Scholar] [CrossRef] [Green Version]
  39. Moyer, R.A.; McGarry Jr, K.G.; Babin, M.C.; Platoff Jr, G.E.; Jett, D.A.; Yeung, D.T. Kinetic analysis of oxime-assisted reactivation of human, Guinea pig, and rat acetylcholinesterase inhibited by the organophosphorus pesticide metabolite Phorate oxon (PHO). Pestic. Biochem. Physiol. 2018, 145, 93–99. [Google Scholar] [CrossRef]
  40. Busardo, F.P.; Pichini, S.; Pellegrini, M.; Montana, A.; Lo Faro, A.F.; Zaami, S.; Graziano, S. Correlation between blood and oral fluid psychoactive drug concentrations and cognitive impairment in driving under the influence of drugs. Curr. Neuropharmacol. 2018, 16, 84–96. [Google Scholar] [CrossRef]
  41. Zafar, R.; Munawar, K.; Nasrullah, A.; Haq, S.; Ghazanfar, H.; Sheikh, A.B.; Khan, A.Y. Acute Renal Failure due to Organophosphate Poisoning: A Case Report. Cureus 2017, 9. [Google Scholar] [CrossRef] [Green Version]
  42. Barbera, N.; Montana, A.; Indorato, F.; Arbouche, N.; Romano, G. Evaluation of the role of toxicological data in discriminating between H2S femoral blood concentration secondary to lethal poisoning and endogenous H2S putrefactive production. J. Forensic Sci. 2017, 62, 392–394. [Google Scholar] [CrossRef] [PubMed]
  43. Maślińska, D.; Lewandowska, I.; Prokopczyk, J. Effect of Prolonged Acetylcholinesterase Inhibition on Postnatal Brain Development in Rabbit I. Level of Serotonin in Different Brain Regions. In Experimental and Clinical Neuropathology; Springer: Berlin/Heidelberg, Germany, 1981; pp. 52–55. [Google Scholar]
  44. Peter, J.V.; Prabhakar, A.T.; Pichamuthu, K. In-laws, insecticide—And a mimic of brain death. Lancet 2008, 371, 622. [Google Scholar] [CrossRef]
  45. Qi, L.; Cao, C.; Hu, L.; Chen, S.; Zhao, X.; Sun, C. Metabonomic analysis of the protective effect of quercetin on the toxicity induced by mixture of organophosphate pesticides in rat urine. Hum. Exp. Toxicol. 2017, 36, 494–507. [Google Scholar] [CrossRef] [PubMed]
  46. Du, L.; Li, S.; Qi, L.; Hou, Y.; Zeng, Y.; Xu, W.; Wang, H.; Zhao, X.; Sun, C. Metabonomic analysis of the joint toxic action of long-term low-level exposure to a mixture of four organophosphate pesticides in rat plasma. Mol. Biosyst. 2014, 10, 1153–1161. [Google Scholar] [CrossRef] [PubMed]
  47. Sun, X.; Xu, W.; Zeng, Y.; Hou, Y.; Guo, L.; Zhao, X.; Sun, C. Metabonomics evaluation of urine from rats administered with Phorate under long-term and low-level exposure by ultra-performance liquid chromatography-mass spectrometry. J. Appl. Toxicol. 2014, 34, 176–183. [Google Scholar] [CrossRef]
  48. Li, S.; Can Cao, H.; Shuang, Y.; Lei, Q.; Xiujuan, Z.; Changhao, S. Effect of quercetin against mixture of four organophosphate pesticides induced nephrotoxicity in rats. Xenobiotica 2016, 46, 225–233. [Google Scholar] [CrossRef]
  49. Mohssen, M. Biochemical and histopathological changes in serum creatinine and kidney induced by inhalation of Thimet (Phorate) in male Swiss albino mouse, Mus musculus. Environ. Res. 2001, 87, 31–36. [Google Scholar] [CrossRef]
  50. Saquib, Q.; Musarrat, J.; Siddiqui, M.A.; Dutta, S.; Dasgupta, S.; Giesy, J.P.; Al-Khedhairy, A.A. Cytotoxic and necrotic responses in human amniotic epithelial (WISH) cells exposed to organophosphate insecticide Phorate. Mutat. Res. Toxicol. Environ. Mutagen. 2012, 744, 125–134. [Google Scholar] [CrossRef]
  51. Saquib, Q.; Al-Khedhairy, A.A.; Siddiqui, M.A.; Roy, A.S.; Dasgupta, S.; Musarrat, J. Preferential binding of insecticide Phorate with sub-domain IIA of human serum albumin induces protein damage and its toxicological significance. Food Chem. Toxicol. 2011, 49, 1787–1795. [Google Scholar] [CrossRef]
  52. Abdollahi, M.; Ranjbar, A.; Shadnia, S.; Nikfar, S.; Rezaiee, A. Pesticides and oxidative stress: A review. Med. Sci. Monit. 2004, 10, 141–147. [Google Scholar]
  53. Fadok, V.A.; Voelker, D.R.; Campbell, P.A.; Cohen, J.J.; Bratton, D.L.; Henson, P.M. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 1992, 148, 2207–2216. [Google Scholar] [PubMed]
  54. Martin, S.; Reutelingsperger, C.P.; McGahon, A.J.; Rader, J.A.; Van Schie, R.C.; LaFace, D.M.; Green, D.R. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: Inhibition by overexpression of Bcl-2 and Abl. J. Exp. Med. 1995, 182, 1545–1556. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Leist, M.; Jäättelä, M. Four deaths and a funeral: From caspases to alternative mechanisms. Nat. Rev. Mol. Cell Biol. 2001, 2, 589–598. [Google Scholar] [CrossRef] [PubMed]
  56. Karalliedde, L.; Senanayake, N. Organophosphorus insecticide poisoning. Br. J. Anaesth. 1989, 63, 736–750. [Google Scholar] [CrossRef] [PubMed]
  57. Betrosian, A.; Balla, M.; Kafiri, G.; Kofinas, G.; Makri, R.; Kakouri, A. Multiple systems organ failure from organophosphate poisoning. J. Toxicol. Clin. Toxicol. 1995, 33, 257–260. [Google Scholar] [CrossRef]
  58. Saquib, Q.; Sabry, M.; Attia, M.A.; Siddiqui, M.; Aboul, S.; Abdulaziz, A.; Al, K.; John, P.G.; Javed, M. Phorate-induced oxidative stress, DNA damage and transcriptional activation of p53 and caspase genes in male Wistar rats. Toxicol. Appl. Pharmacol. 2012, 259, 54–65. [Google Scholar] [CrossRef]
Healthcare 09 00131 g001 550
Figure 1. (a) the stomach’s opening: stomach contained 100 mL of brown color; (b) chromatogram of the case.
Figure 1. (a) the stomach’s opening: stomach contained 100 mL of brown color; (b) chromatogram of the case.
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Healthcare 09 00131 g002 550
Figure 2. Flow diagram illustrating included and excluded studies in this systematic review.
Figure 2. Flow diagram illustrating included and excluded studies in this systematic review.
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Healthcare 09 00131 g003 550
Figure 3. Histological findings in the kidney: (a) glomerulus hypercellularity; (b) deposition of eosin-positive material in the tubules; (c) increased space between Bowman’s capsule and glomerulus; (d) increased cellularity in the glomerulus.
Figure 3. Histological findings in the kidney: (a) glomerulus hypercellularity; (b) deposition of eosin-positive material in the tubules; (c) increased space between Bowman’s capsule and glomerulus; (d) increased cellularity in the glomerulus.
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Table
Table 1. Characteristics of eligible studies (animals and humans).
Table 1. Characteristics of eligible studies (animals and humans).
ReferenceStudy DesignTargetExposureIntervention/OutcomeMain Findings
Khatiwada et al., 2012 [3]case reportn.2 women:
(1) 30-year-old
(2) 80-year-old		acuteunintentional ingestion of phorate granules mistaken for food (sesame seeds)30-year-old woman dead on arrival at the emergency department; 80-year-old woman survived after resuscitation procedures.
Peter et al., 2008 [44]case report30-year-old femaleacuteimpulsively swallowed 50 mL of phorate after a family disputesurvived after hospital treatment.
Qi et al., 2017 [45]prospective, observationalrats;
urine analysis		Chronicrats were given a
mixture of four op pesticides (dimethoate, acephate, dichlorvos, and phorate) for 90 days.		Alteration of kidney function, modification of DNAwith alteration of the metabolism of fatty acids, energy and sex hormones, antioxidant defense system.
Du et al., 2014 [46]prospective, observationalrats;
the plasma was analyzed		chronicmixture of four op pesticides (dimethoate, acephate, dichlorvos, and phorate) for 24 weekskidney damage of tubular cell, granular and vascular degeneration.
Sun et al., 2012 [47]prospective, observationalrats;
metabonomics evaluation of urine by uplc-ms;
long-term
and low-level exposure		chronicphorate daily in drinking water at low doses of 0.05, 0.15 or 0.45 mg/kg body weight (bw) for 24 weeks consecutivelykidney damage: the levels of creatinine (cr) and urea nitrogen (bun) were significantly elevated in the high-dose group, indicating kidney damage after exposure to phorate.
Li et al., 2016 [48]prospective, observationalrats;
the authors examined the effect of quercetina		chronicmixture of four organophosphates (dichlorvos, acephate, dimethoate and phorate) for 90 dayskidney damage: histopathological examination showed extensive cell vacuolar denaturation and desquamation of the epithelial lining of the tubules; renal damage by impairing the reabsorption capacity of the proximal tubules and by decreasing glomerular filtration rate.
Mohssen 2001 [49] prospective, observationalratschronicsubchronic inhalation of the recommended field dose of phorate (20 kg/ha).kidney damage: impairment of glomerular function and tubular damage with mild to severe multifocal cloudy and hydropic degeneration (edema) with necrosis in kidney tubules.
Saquib et al., 2012 [50]prospective, observationalratschronic14 days of varying oral doses of phorate of 0.046, 0.092 or 0.184 mg kidney damage: infiltration of leukocytes in the bowman’s space with dilated blood vessels, and renal necrosis.
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Montana, A.; Rapisarda, V.; Esposito, M.; Amico, F.; Cocimano, G.; Nunno, N.D.; Ledda, C.; Salerno, M. A Rare Case of Suicide by Ingestion of Phorate: A Case Report and a Review of the Literature. Healthcare 2021, 9, 131. https://doi.org/10.3390/healthcare9020131

AMA Style

Montana A, Rapisarda V, Esposito M, Amico F, Cocimano G, Nunno ND, Ledda C, Salerno M. A Rare Case of Suicide by Ingestion of Phorate: A Case Report and a Review of the Literature. Healthcare. 2021; 9(2):131. https://doi.org/10.3390/healthcare9020131

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Montana, Angelo, Venerando Rapisarda, Massimiliano Esposito, Francesco Amico, Giuseppe Cocimano, Nunzio Di Nunno, Caterina Ledda, and Monica Salerno. 2021. "A Rare Case of Suicide by Ingestion of Phorate: A Case Report and a Review of the Literature" Healthcare 9, no. 2: 131. https://doi.org/10.3390/healthcare9020131

APA Style

Montana, A., Rapisarda, V., Esposito, M., Amico, F., Cocimano, G., Nunno, N. D., Ledda, C., & Salerno, M. (2021). A Rare Case of Suicide by Ingestion of Phorate: A Case Report and a Review of the Literature. Healthcare, 9(2), 131. https://doi.org/10.3390/healthcare9020131

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