Poisons and Drugs Used in Homicidal Poisoning: A Systematic Review

Search Strategy

We conducted the study in accordance with the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched PubMed (pubmed.gov) and Google Scholar (scholar.google.com) using “Homicidal poisoning” OR “Criminal poisoning” as keyword words. We searched all articles from January 1, 2010 to September 30, 2023 that described human cases of homicidal poisoning.

Inclusion and Exclusion Criteria

All type of articles describing homicidal poisoning were included. Forensic-based studies and reports of forensic cases (including clinical presentations, autopsy findings, postmortem histopathological and toxicological analysis) were included. Finally, we excluded articles that were had insufficient data, no toxicological analysis data or undetected poisonous agent. We evaluated the titles and abstracts, and full-text of the articles. Also, non-English publications were excluded.

Data Collection

We extracted the following data, when available: the number, age, and gender of victim(s), route of exposure (ingestion, injection, dermal), poison name, poison’s vehicle (e.g. food, drinks, pharmaceutical dosage form), offender identity and relationship with victim(s), clinical signs and symptoms, poisoning outcome (survived or death), forensic autopsy findings (including postmortem toxicological and histopathological analysis).

Drugs as a Tool Used in Homicidal Poisoning

A notable issue in this study, co-administration and a polydrug pattern including benzodiazepines (midazolam, clonazepam, alprazolam, bromazepam, oxazepam), Z-drugs (zolpidem), antipsychotics (cyamemazine, haloperidol, risperidone, tiapride), antihistamines (Hydroxyzine, cetirizine), antidepressants (amitriptyline, venlafaxine) and analgesics (paracetamol) as a cocktail for homicidal poisoning in elder victims.

Antipsychotics are commonly used to treat schizophrenia, bipolar disorders, depression, and other conditions. Antipsychotics are classified as typical first- generation or atypical second-generation drugs [53]. They have special warnings for use in the elderly patients with dementia-related psychosis that includes an increased risk for fatalities and cerebrovascular accidents [53]. Also, sudden cardiac death has become a significant clinical concern when prescribing antipsychotic drugs, especially to elder patients with dementia. Actually, patients treated with both the first- and second-generation versions and current use of tricyclic antidepressant and benzodiazepines experienced an increased incidence of fatalities. Co-morbidity conditions, especially heart disease, in the administration of antipsychotics drugs have been associated with sudden cardiac death [54]. From this view, administration of cocktail of these drugs as a homicidal tool by offenders should be considered especially in elder patients nursing house in suspicious and undetermined death. In reviewed cases intermittent episodes of malaise, decreased of vigilance, acute respiratory distress and coma have been reported as clinical presentations of the victims due to covert oral administration of antipsychotics plus other central depressant medicines via meal in the elder patients.

Heavy Metals Used in Homicidal Poisoning

In our study, arsenic had one reported homicidal intent of poisoning but it had high number of poisoned victims in this episode. This report demonstrates an outbreak of apparent food-borne illness following a church gathering. Gastrointestinal symptoms among church attendees were initially attributed to consumption of leftover sandwiches that had been served the previous day. However, a rapid epidemiological and laboratory assessment revealed the etiology of illness was not food-borne in origin. It was due to a criminal act via deliberate arsenic contamination of the brewed coffee by one of the church members [18].

Arsenic, a metalloid, is one of the oldest poisons known to humans. Historically, its applications were including pesticides (insecticides, fungicides, herbicides), ceramic enamels, preservatives, glass manufacturing, firework, medicinal use (antibacterial, dermatological and hematological agents), and paint. Acute arsenic poisoning is rare in the recent years. Arsenic compounds are organic arsenicals and pentavalent or trivalent inorganic arsenic. The trivalent derivatives are more toxic than pentavalent forms [55, 56]. Arsenic-related deaths due to acute poisoning occur as a result of accidental, intentional (homicides and suicides) poisoning [55, 56]. Clinical presentations of acute arsenic poisoning are usually apparent when the poison is administered orally, inhalation or by injection [54]. Clinical signs and symptoms of acute arsenic poisoning are predominantly gastrointestinal, cardiovascular, neurologic, and renal [56]. Acute arsenic poisoning is associated initially with nausea, vomiting, abdominal pain, and severe diarrhea. Encephalopathy and peripheral neuropathy are reported [57]. Acute arsenic poisoning may result in death. A garlic- like odor on the breath or in perspiration is suggestive of arsenic poisoning. Death from arsenic is generally caused by circulatory collapse, associated with intense gastroenteritis, capillary injury that produces vasodilatation, transudation of plasma, and shock and multiorgan failure [56]. Arsenic toxicity induces by inhibition of many enzymes, especially those involved in cellular energy pathways and DNA synthesis and repair [57].

Thallium is another common poison used in the homicidal poisoning in this study. In unique case a thallium toxicosis in Italy in 2017 due to deliberate adulteration of an herbal infusion with thallium sulphate by the grandson of the victims occurred in eight members of a family, three of them died because of the poisoning [17]. Thallium is a toxic heavy metal used in concrete, optical lenses, dyeing and pigments, jewelry, electronic, for green fireworks and military industries. Thallium in the form of water soluble salts (sulfate, acetate and carbonate), with a concentration of 2% as a rat poison killer. Thallium is colorless, odorless, water- soluble, and tasteless, therefore, it often passes unnoticed. It is extremely toxic, and the lethal dose is estimated to be 10–15 mg/kg [58]. The diagnosis of criminal thallium poisoning in general clinical practice is quite hard and may be misdiagnosed due to the wide range of symptoms of the poisoning with other common diseases [17, 58]. The acute thallium poisoning is divided into three phases.

The first phase is the intravascular distribution and lasts approximately for the first 4 h. Then, the poison is distributed in the central nervous system and this second phase lasts for 48 h. The third phase is the elimination phase mainly through the gastrointestinal and renal system which begins 24 h later.

Gastrointestinal, neurological, and dermatological symptoms are the main symptoms in acute thallium poisoning [58, 59]. The first symptoms of poisoning, within the first 48 hours from the poisoning is include gastrointestinal symptoms (abdominal pain, cramps, nausea, vomiting, fever and constipation), acute cardiotoxic effects, hematologic manifestations (anemia and thrombocytopenia), followed by neurotoxicological symptoms (tremor, acute and progressive paralysis of the limbs, coma) [59]. Within 3-4 weeks, usually, alopecia appears mainly to the eyebrows and the auxiliary area. The death can occur due to cardio-circulatory failure or multi-organ failure [58, 59]. Thallium acts in a way similar to potassium but with an affinity 10 times higher, replacing this latter substance in a series of enzymatic complexes, especially mitochondrial, other mechanisms are suspected of having an important role in these processes as the already cited oxidative stress, the interruption of the potassium- regulated homeostasis and of the glutathione metabolism [57, 58, 59].

Elemental mercury and its salts was a common cause of homicidal poisoning in the present study.

Mercury is a toxic heavy metal has three forms including metallic, inorganic, and organic compounds.

Metallic mercury is volatile and highly lipophilic [21, 60] Metallic mercury poisoning is usually caused through inhalation of its vapor [21]. Systemic symptoms in acute mercury poisoning are headache, pyrexia, chill, fatigue, sore throat, dizzy, itching, skin rash, body aches, and waist soreness, soft tissue necrosis, respiratory symptoms (chest pain, cough, bloody sputum, sweatiness, hemoptysis, dyspnea). In addition, gastrointestinal presentations (abdominal pain, nausea, vomiting, anorexia, diarrhea, oral ulcers and gingival bleeding), neurological deficits (tremors, cerebellar dysfunction, generalized tonic-clonic seizures, peripheral axonopathy and mental abnormalities) and liver and kidney damage have been reported in acute exposure of metallic mercury [21, 60].

Metallic mercury poisoning through intravenous administration is quite rare, especially for homicide [21]. Injection of metallic mercury can lead to a rapid increase of circular mercury in a short time, and finally distributes throughout the body. It can be easily misdiagnosed when no history of mercury exposure is available, especially in homicide cases [21].

Pesticides Used in Homicidal Poisoning

Pesticides defined as a chemical or biological agents used to repel or kill the agricultural and veterinary pests. Pesticides are potent and lethal toxic substances that are also being infamously used for homicidal intent due to their easy availability and rapid action. In this review, organophosphates and rodenticides were the most commonly used pesticides, and ingestion was the most common route of administration; however, other modes of administration, such as through intraperitoneal injection, were also reported. The regulations for the production, distribution, sale, and use of pesticides and sever monitoring programs can help control the prevalence of these type of poisoning [61]. In the present study, pesticides including paraquat (N,N′-dimethyl- 4,4′-bipyridinium dichloride; a herbicide), carbofuran (a carbamate insecticide and nematocide), chlorpyrifos (an organophosphate pesticide) and cypermethrin (a synthetic pyrethroid used as an insecticide), brodifacoum (is a highly lethal 4-hydroxycoumarin vitamin K antagonist anticoagulant poison, a rodenticide), strychnine (an alkaloid and used as a rodenticide) were the reported poisons used in homicidal poisoning mainly in countries like as India, Sri Lanka and South Korea. This findings are similar to previous studies especially from developing countries which public availability to these poisons is easer [10, 29, 30, 31, 32, 33].

Poisons Used in the Recent Political Homicidal Poisoning

Poisons used in political homicidal poisoning in famous cases according to timeline and place of incident were ricin (Georgi Markov, 11 September 1978, London, UK), fentanyl (Khaled Mashal, 25 September 1997, Amman, Jordan),TCDD dioxin (Viktor Andriyovych Yushchenko, 5 August 2004, Kyiv, Ukraine), polonium-210 (210Po) radioisotope (Yasser Arafat, 11 November 2004, Percy, France and Alexander Litvinenko, 1 November 2006, London, UK), VX (Kim Jong- Nam, 13 February 2017, Kuala Lumpur, Malaysia), and Novichock (Sergei Skripal and his daughter Yulia, 4 March 2018, London, UK, and Alexei Navalny, 20 August 2020, Tomsk, Russia) [3, 62, 63]. As a notable fact, contemporary poisons, are based on the use of synthetic substances from the organophosphorus-based nerve agents and radioactive isotopes instead of biotoxins. Some of these poisons (especially, polonium-210 and ricin), resulted initially in a clinical presentations that was misdiagnosed with infections, chronic disease or chemicals poisoning like as heavy metals and chemotherapeutic agents or radiations [3, 24].

Polonium-210 (210Po) is an isotope of Polonium and a natural radioactive element that it undergoes alpha decay to stable lead-206, with occasional excitation in the nucleus and emission of 803keV gamma rays. Its half-life is 138 days and its biological half-life is human body approximately 30-50 days [24, 25, 63]. 210Po is used in various industrial processes and as a lightweight heat source to power thermoelectric cells in satellites. Also, Polonium-210 was used in initiators for atomic bombs through the alpha and neutron reaction with beryllium. 210Po is extremely toxic as a radiotoxic agent for man. One microgram of 210Po being more than enough to kill the average adult, it is 250,000 fold more toxic than hydrogen cyanide by weight [63]. Lethal dose 50 (LD50) of 210Po considered as 50ng (for oral route) and 10ng (in inhalation route). This is a consequence of its ionizing alpha radiation, as high energy alpha particles are especially damaging to organic tissues. However, 210Po does not pose a radiation hazard when contained outside the body. The alpha particles it produces cannot penetrate the outer layer of dead skin cells [63].

Intake of 210Po occurs primarily through contaminated food, water or air, as well as through open wounds. It forms water-soluble, colorless salts that are readily absorbed across biological membranes. Post ingestion, 210Po concentrates in red blood cells and soft tissues (with highest concentration in the liver, spleen, bone marrow, kidneys, gonads and skin). 210Po is excreted in urine, bile, sweat, and possibly in breath and is also deposited in hair. After ingestion, unabsorbed 210Po is present in the faces [64, 65].

However, It is not widely available and used in political homicidal poisoning by governmental secret security and intelligence agencies for assassination and terroristic acts of political activists and leaders. If the absorbed dose is sufficiently large, polonium-210 can cause Acute Radiation Syndrome (ARS). Clinical presentations after oral intake of 210Po are gastrointestinal symptoms such as nausea, vomiting, anorexia, abdominal cramps and watery and bloody diarrhea. Additional symptoms include bleeding, alopecia, lymphopenia (especially without elevated temperature), thrombocytopenia and leukocytes (occurring after a few days or weeks after gastrointestinal symptoms). Followed by a latent phase during which there is some clinical improvement. Subsequently, the characteristic bone marrow suppression, gastrointestinal or cardiovascular/ central nervous system (confusion, loss of consciousness, seizure, cerebral edema, cerebral hemorrhage and a burning sensation of the skin). Extreme immunosuppression and mucosal bleeding secondary to myelosuppression and pancytopenia. Severe electrolyte imbalances from diarrhea and dehydration can also be seen. The triad of early emesis followed by alopecia and myelosuppression is typical of ARS [65]. Death often occurs within 2–3 weeks of the onset of the poisoning and due to multiorgan failure [66].

Recently, organophosphate nerve agents such as VX and novichock have been used in chemical terrorism acts for political homicidal poisoning [3, 51, 52].

VX (venomous agent X) is an extremely toxic organophosphorus nerve agent class of chemical weapons. In recent years, pure form of VX was used in the assassination of Kim Jong-nam. Physically, pure form of VX is an amber- colored, odorless, tasteless and oily liquid [3, 67]. The LD50 of VX through dermal contact in a 70 kg human is reported to be 5–10 mg [3, 67].

VX fatalities occur with exposure via inhalation, ingestion or dermal contact. VX as a nerve agent severely disrupt the signaling between the nervous and muscular systems, by irreversible inhibition of acetylcholinesterase and increasing the amount of acetylcholine in the neuromuscular junction, resulting neuromuscular blockade, flaccid paralysis of all the muscles in the body including the diaphragm, and death by asphyxiation [67].

The symptoms and signs of VX acute poisoning are hyperstimulation of muscarinic receptors such as miosis, nausea, vomiting, abdominal cramps, salivation, lacrimation, hyperhidrosis, rhinorrhea, bronchorrhea, bronchospasms, dyspnea, bradycardia, and hypotension. It also hyper- stimulates nicotinic receptor at the neuromuscular junction and results in fasciculations, muscle weakness, and, ultimately paralysis. Nicotinic receptor hyperstimulation also induces hypertension and tachycardia [67]. Dermal exposure with VX causes the appearance of cholinergic toxidrome. It can induce immediate bronchoconstriction or respiratory distress in the lung spaces [67].

Novichoks (in Russian language means “newcomer”) are the suspected nerve agents to carry out political assassinations in case of the Skripal and Navalny poisoning [3, 68, 69]. Novichoks are referred as fourth generation chemical weapons with a group of organophosphorus-based compounds [68]. Novichoks are most commonly found in stable forms as liquid and fine powder forms [3]. The high lipophilicity of these compounds prolongs their detection time in the body. Novichocks may be up to 5-8 times more toxic than VX [3, 68].

The mechanism of action of novichocks involves irreversible inhibition of acetylcholinesterase resulting in cholinergic toxidrome [68, 69]. Symptoms resulting from overstimulation of muscarinic receptors include skin flushing, miosis, visual disturbances, salivation, lacrimation, bronchorrhea, bronchospasm, coughing, dyspnea, sweating, abdominal carmps, diarrhea, bradycardia and involuntary urination and defecation. Overstimulation of nicotinic receptors is responsible for tremor, seizure, muscle weakness up to complete paralysis, tachycardia, hypertension [68, 69].

Biotoxins Used in the Homicidal Poisoning

Application of biotoxins such as tetrodotoxin (TTX), herbal toxin (colchicine) and snake venom in forcible snake bite as homicidal poisoning were notable in this review.

Tetrodotoxin (TTX) is a potent marine neurotoxin that was first identified in puffer fish (mainly in the liver and gonads) and in some fish such as globefish, sunfish, triggerfish and toadfish (order Tetraodontiformes), and in some amphibian, octopus, and shellfish species. Also, it has been isolated from an array of taxa that host TTX-producing

bacteria. TTX is a crystalline, colorless and weakly basic organic substance. TTX is a sodium channel blocker inhibits the firing of action potentials in neurons by binding to the voltage-gated sodium channels in nerve cell membranes and blocking the passage of sodium ions into the neuron.

TTX poisonings were most commonly reported as a food poisoning from countries like Japan, Thailand, and China, but today the risk of TTX poisoning is spreading around the world. Recent studies have shown that TTX-containing fish are being found in other regions of the Pacific, Southeast Asia and in the Indian Ocean, and in the Mediterranean Sea [70, 71].

TTX is extremely toxic. The oral LD50 in mice as 334 μg/kg. TTX is even more dangerous if administered intravenously; the amount needed to reach a lethal dose by injection is 8 μg/ kg in mice [72].

TTX poisoning symptoms typically develop within 30 minutes up to 4 hours of ingestion, in fatal cases, the symptoms are usually present within 10-20 minutes of ingestion. Orolingual numbness followed by developing it in the extremities (acroparesthesia), salivation, sweating, headache, weakness, lethargy, incoordination, tremor, paralysis, bluish skin, loss of voice, dysphasia and seizures. The GI symptoms are often severe and include nausea, vomiting, diarrhea, and abdominal cramps. Death is usually secondary to cardiorespiratory failure [70, 71, 72]. The victim usually exhibits shortness of breath, mydriasis, complete atrioventricular block and hypotension. Mental impairment and cardiac dysrhythmia may occur. Although, the victim completely paralyzed, may be conscious and in some cases completely understandable until shortly before death. However, some victims enter a coma [70, 71, 72].

A rare and strange homicidal poisoning case reported was forced envenomation by snake bite [50]. Snake bite is accidental in urban, suburban and rural areas and desert and few cases were reported to commit suicide. Homicidal snake poisoning is so rare. It was known in ancient world by executing capital punishment by throwing the victim into a pit full of snakes. Or to ask the victim to put his hand inside a small basket harboring a deadly snake. Murder a victim by direct snake bite is so rare. In this case report, killing three children (they were 9-, 6-, and 4-years old girls) by forced snake bite. In forensic investigations, it was found that the father disliked these three children as they were girls. He married another woman and had a male baby. The father decided to get rid of his girl children. To achieve his plan, he trained to become snake charmer and bought a snake (Egyptian cobra) the father forced the snake to bite the three children several times and left them to die. At last, he burned the snake.

Egyptian cobra (Naja haje haje), is widely distributed in Africa and the Middle East. The LD50, its venom is 0.12 µg/g. Envenomation causes local pain and swelling, and may be associated with blistering at the bite site. Neurotoxic and systemic symptoms develop within few hours, and deaths have occurred within 6–16 h after large snakes’ bites, despite the use of antivenom and mechanical ventilation [73]. Four toxins (CM-7, CM-8, CM-9 and CM-10b) were purified from Egyptian cobra venom and belong to a cytotoxin group [74]. Recently, the researchers purified an approximately 15 kDa basic phospholipase A2 enzyme from its venom [75].

Application of Gloriosa superba seeds (contain colchicine) for homicidal poisoning has been reported [49]. Colchicine, a natural tricyclic and lipid-soluble alkaloid found in plants such as the Colchicum autumnale and Gloriosa superba has been used for the treatment and prevention of gout and for familial Mediterranean fever (FMF) and many immunological diseases, but if misused can result in fatal consequences. Accidental poisoning of colchicine as a result of consumption of the herb G. superba has been reported, previously [76]. Colchicine has a narrow therapeutic index (1.2–2.4 mg/day in adults) and long half-life and intentional and unintentional poisoning is common and often associated with a poor outcome. It is readily absorbed after oral ingestion. It is primarily metabolized by the liver and undergoes extensive first-pass metabolism and significant enterohepatic recirculation. It widely distributed and binds to intracellular parts. It is also excreted by the kidneys. High mortality rate was reported after acute ingestions exceeding 0.5 mg/kg. The lowest reported lethal doses of oral colchicine are 7-26 mg [77].

Colchicine toxicity is an extension of its mechanism of action - binding to tubulin and disrupting the cell transport system. Colchicine can inhibit protein synthesis and assembly, decreased endocytosis and exocytosis and cellular motility, altered cell morphology, disruption in mitosis, and interrupted cardiac conduction and contractility. Finally, multisystem organ dysfunction and failure has occurred during 24-72 hours. Colchicine typical toxidrome consistence of gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia [77, 78].

Colchicine poisoning clinical presentations were in three sequential phases: phase 1: 10-24 h after ingestion, gastrointestinal phase mimicking gastroenteritis (profuse vomiting and diarrhea, which can be bloody, abdominal cramps). Phase 2: 24 h to 7 days after ingestion, metabolic acidosis, hypovolumic shock, myelosupression (including anemia, leucopenia, and thrombocytopenia) and multi-organ dysfunction including oliguric renal failure, liver dysfunction, acute myocardial injury and respiratory failure. Death results from rapidly progressive multi-organ failure and sepsis.

Delayed presentation, pre-existing renal or liver impairment are associated with poor prognosis. 3) Recovery typically occurs within a few weeks of ingestion. The fatality rate in colchicine poisoning is 50% [77, 78]

The Role of Forensic Investigations, Autopsy Findings and Postmortem Toxicological Analysis for Determining the Homicidal Poisoning

A Comprehensive forensic investigation including crime scene and evidences analysis and postmortem examination in poisoning-related fatalities is a crucial role to establish the cause and manner of death. A comprehensive analysis of homicidal poisoning fatalities involving forensic investigative data about crime scene evidences evaluation and circumstances, clinical toxicology findings of the poisoned victim who admitted in a hospital, autopsy findings, postmortem histopathological and toxicological results are a fundamental part to diagnosis of fatal homicidal poisoning. Autopsy and postmortem histopathological findings indicative of an poisoned death are scarce and mostly unspecific and majority of pharmaceutical drugs poisonings will leave no characteristic findings at autopsy. Indeed, the most common findings are organ edema and congestion such as pulmonary edema and liver congestion, which are common in all kinds of deaths. However, the external and internal examinations of victim’s corpse gives a valuable data about cause and manner of death. For example, residues of powder or colored material in stomach content might indicate tablet or capsule remains in a oral poisoning. Smell of body (bitter almond in cyanide or nitrobenzen poisoning and garlic odor in organophosphate, phosphorous, phosphine and arsenic deaths) and livor mortis (also known as postmortem hypostasis or postmortem lividity) like cherry red lividity in carbon monoxide poisoning have been observed. Injections marks are important clues for an parental administration of poison or drugs. Noncardiogenic pulmonary edema resulting in heavy, enlarged lungs with edema and congestion along with froth in the airways is typically found in opioid toxicity deaths. Liver necrosis can be the result of paracetamol (acetaminophen) overdose. A massive spontaneous brain hemorrhage and edema, or gastrointestinal bleeding may indicate intake of anticoagulants and radiotoxic agents. Some histopathological findings like as dilated cardiomyopathy (ethanol use) and steatotic or cirrhotic in cases of chronic alcoholic abusers were observed [79].

Postmortem toxicological analysis on biological fluids and tissues including blood (femoral), urine, stomach content, bile, vitreous humor, cerebrospinal fluid, bone marrow, liver, lung, kidney and muscle tissues and hair are important for detection of drugs and poisons in fatal poisonings [80, 81, 82]. There are a wide variety of analytical techniques available for the analysis of toxic substances in biological samples.

The most common techniques used in forensic toxicology can be grouped into spectrophotometry [e.g. Atomic Absorption Spectrophotometry (AAS), Ultraviolet-Visible Spectrophotometry (UV-VIS)], immunoassay [Enzyme- Linked Immunosorbent Assay (ELISA), Radioimmunoassay (RIA), Fluorescence Polarization Immunoassay (FPIA), Cloned Enzyme Donor Immunoassay (CEDIA), and Enzyme Multiplied Immunoassay Technique (EMIT)], chromatography methods (High-Performance and Ultrahigh- Performance Liquid Chromatography (HPLC and UHPLC), Gas-Chromatography with Flame Ionization Detector (GC- FID), or specific detectors for GC like Electron Capture Detector (ECD) and Nitrogen Phosphorus Detector (NPD), Gas-Chromatography with Mass Spectrometry (GC-MS) have been used in forensic toxicology analysis. Also, more sophisticated techniques like Liquid Chromatography with tandem mass spectrometry (LC-MS-MS), tandem GC-MS, Inductively coupled plasma mass spectrometry (ICP-MS) can be used to measure drugs and poisons at trace levels in biological samples [79, 83]. In addition, alpha-particle spectroscopy and gamma-ray spectroscopy can be used for the qualitative analysis of the energy spectra in radioisotopes induced poisoning [84].