Clinical toxicology of exposures to chemicals from clandestine drug laboratories: a literature review

Abstract

Introduction

The synthesis of clandestine drugs is a widespread worldwide phenomenon, with clandestine drug laboratories occurring both in rural and urban areas. There is considerable unfamiliarity among medical professionals about the health risks that are associated with chemicals used in clandestine drug laboratories.

Objective

To evaluate the adverse health effects resulting from exposure to chemicals involved in the production of clandestine drugs.

Methods

The US National Library of Medicine PubMed database and the Excerpta Medica database (EMBASE) were searched from their date of inception to October 26, 2021 using combinations of relevant search terms. This yielded 1,558 unique articles, which were subjected to two eligibility criteria: (i) exposure to clandestine drug laboratory chemicals resulting in adverse health effects; (ii) subjects were human. A total of 22 unique articles were retrieved, consisting of 10 reviews, eight case reports/series and four retrospective studies. Further searches among the references cited in these publications yielded another seven case reports/series and six retrospective studies.

Results

Inhalation: Surveillance studies reported respiratory symptoms (including cough, throat irritation, nasal irritation, and dyspnea) in 59% (n = 1,657 of 2,803) of those exposed. The case reports/series described respiratory symptoms in 43% of the cases (n = 36 of 84). Lung edema was reported occasionally (n = 2). Eye exposure: Surveillance studies reported eye irritation and burns in 23% (n = 647 of 2,803) of those exposed. The case reports/series described ocular adverse events in 36% of the cases (n = 30 of 84). More severe ocular effects, such as corneal damage and conjunctival necrosis, were reported after direct eye contact with caustic fluids. Skin exposure: Surveillance studies reported dermal effects, ranging from skin irritation to severe burns, in 6% of those exposed (n = 174 of 2,803). The case reports/series described dermal effects in 30% of the cases (n = 25 of 84). Ingestion: Gastrointestinal burns were observed after ingestion of caustic substances in 5% of the patients reported in the case reports/series (n = 4 of 84). Systemic effects: Surveillance studies reported headache and dizziness in 31% (n = 882 of 2,803) and 7% (n = 187 of 2,803) of those exposed, respectively. The case reports/series described sympathomimetic effects, including mydriasis, hypertension, tachycardia, in 4% of the cases (n = 3 of 84). Fatalities: Surveillance studies reported death in 1% of those exposed (n = 29 of 2803). Ten percent of the people reported in the cases report/series died (n = 8 of 84). Death was reported after inhalation of phosphine (n = 5), hydrogen sulfide (n = 1), methanol (n = 1), and after ingestion of sulfuric acid (n = 1).

Conclusions

Exposure to chemicals involved in the production of clandestine drugs mostly resulted in mild to moderate respiratory, ocular or dermal effects, usually caused by caustic chemicals or solvents. Systemic effects were generally mild, but severe symptoms and eight deaths were reported after exposure to phosphine, hydrogen sulfide, methanol and sulfuric acid.

Keywords:

• Clandestine
• laboratory
• toxicology
• drug
• adverse effects

Introduction

Due to the constant worldwide demand for illicit drugs, clandestine drug laboratories can be found throughout the world [1,2]. Clandestine drug laboratories are set up to synthesize illicit drugs or their precursors, to further modify drugs, to extract drugs from carrier materials or to adulterate/portion drugs. The methods of clandestine drug synthesis can vary between laboratories and depend on the availability of the appropriate precursors, the availability of laboratory equipment and the knowledge and experience of the “cook”/drug producer. Drugs are synthesized both in professional laboratories as well as under primitive conditions, even at home, for instance within urban communities, with all associated risks [2]. The low safety standards of most clandestine drug laboratories pose health risks for the drug producer, as well as bystanders, including first responders, members of the general public and hazardous material clean-up workers.

Drug synthesis potentially involves exposure to hazardous chemicals which could result in serious health effects. Hazardous chemicals used in bulk in clandestine drug laboratories include toxic alcohols, organic solvents, acidic and alkaline solutions [2–4]. For instance, methanol is used as a solvent during the synthesis of MDMA (3,4-methylenedioxymetamfetamine), including the Wacker oxidation from safrole to piperonyl methyl ketone [37]. During these processes, methanol evaporates, and without adequate ventilation, harmful airborne concentrations may be reached. Organic solvents, including heptane and toluene, are used for extraction of intermediate or end products [2,5]. Anhydrous ammonia is another hazardous chemical commonly used in the synthesis of illicit drugs. This chemical is used, together with an alkali metal (usually lithium or sodium), to reduce ephedrine or pseudoephedrine to form metamfetamine in the so-called Birch reduction [6].

Analyses in experimental clandestine drug laboratory set-ups showed anhydrous ammonia concentrations exceeding those dangerous to life and health [5]. A simplified version of the Birch reduction, the so-called “one-pot” or “shake-and-bake” method, can easily be performed in a small reaction volume, such as soda bottles. This synthesis method is used to convert pseudoephedrine hydrochloride tablets into small amounts of metamfetamine [7]. The combination of an alkaline, highly reactive reaction mixture and minimal expertise, poses a very high risk of exposure to chemicals and their adverse effects.

Acidic chemicals are also used during the synthesis of illicit drugs. For example, both sulfuric acid and hydrochloric acid are used in the process of salting out metamfetamine [8]. Uncontrolled release of such chemicals, for instance during a fire or explosion, may result in respiratory damage or chemical burns in case of eye or skin contact.

Hazardous substances may also be formed during drug synthesis. First, the end products themselves may pose health risks, for instance when clandestine drug laboratories are abandoned and new residents are exposed to remaining drug residues [5,9]. Second, several hazardous substances may be formed during the synthesis of illicit drugs. Phosphine is a possible byproduct during the synthesis of metamfetamine via the ephedrine/hydriodic acid/red phosphorus method. Experimental studies mimicking metamfetamine synthesis in clandestine drug laboratories showed that relative high phosphine concentrations could be reached during the “cooking process” [5].

In this review, we clarify which adverse health effects are potentially associated with chemicals from clandestine drug laboratories and which participants (bystanders, producers, first responders) are most usually involved.

Objectives

To evaluate the adverse health effects reported in the literature resulting from exposure to chemicals involved in the production of clandestine drugs.

Methods

The US National Library of Medicine PubMed database and the Excerpta Medica database (EMBASE) were searched from their date of inception to October 26, 2021 using combinations of relevant search terms. PubMed search terms included: “clandestine drug laboratory” [All Fields], illegal drug laboratory [Title/Abstract], “drug waste”[All Fields], “clandestine drug synthesis” [All Fields], “clandestine drug” [All Fields], illicit drug laboratory [All Fields] (filter: Case reports), illicit drug synthesis [All Fields] (filter: Case reports), “illegal drug production” [All Fields] (filter: Case reports), clandestine drug laboratory [All Fields], precursor AND clandestine [all fields]. A total of 629 unique articles were found.

The Embase search terms included: “clandestine drug laboratory” (quick search), illegal drug laboratory (Title/Abstract/Author keywords), “drug waste” (quick search), “clandestine drug synthesis” (quick search), clandestine drug synthesis (quick search), “clandestine drug” (quick search), illicit drug laboratory (quick search) (filter: case report), illicit drug synthesis (quick search) (filter: case report), “illegal drug production” (quick search), illegal drug production (quick search), clandestine drug laboratory (quick search), precursor AND clandestine. A total of 1,216 unique articles were found.

There were 287 duplicates, thus reducing the total from 1,845 to 1,558 articles. These 1,558 articles were then hand searched. Articles were eligible for this review when:

1. they described the undesired exposures to chemicals used in clandestine drug laboratories resulting in adverse health effects; and

2. the subjects were human.

Most of the articles found fell outside the scope of this review. Articles concerning exposures to illicit drugs of abuse not in the context of clandestine drug laboratory events (n = 309), clandestine drug laboratories without exposures to chemicals (n = 21), contaminations, adulterations and impurities in drugs of abuse (n = 63), illicit drug chemicals or medicines in waste/environment (n = 119), toxicology, pharmacokinetics, analysis of illicit drugs of abuse (n = 180), chemistry of illicit drugs of abuse (n = 77) legislation, drug control, trends in illicit drugs (n = 104), or other unrelated subjects (oncology, cases negative for illicit drugs, COVID-19, drug adverse effects, steroids, counterfeit medication, formulations, therapy, false positive drug screens, doping, fat burners, bacterial infections, alcohol, medicinal cannabis, etc.)(n = 663) were all omitted.

The combination of the results of the PubMed and Embase study resulted in a total of 22 unique articles, consisting of 10 reviews, eight case reports/series and four retrospective surveillance studies (two studies involving inventory questionnaires about health effects among law enforcement personnel, two studies involving analyses of an emergency events surveillance database).

Further search among the references cited in these publications yielded another seven case reports/series and six retrospective surveillance studies (three analyses of an emergency events surveillance database, one analysis of a poison control center data, one analysis of medical records, and one inventory questionnaire) involving adverse effects after clandestine drug laboratory chemical exposure, making a total of 35 articles.

The following definitions were used to characterize the demographics of clandestine drug laboratory-related exposures: child: a person <18 years old; first responder: police officer, firefighter, healthcare professional, forensic expert; drug producer: person involved in producing drugs in a clandestine drug laboratory; bystander: people other than first responders and drug producers who were exposed to clandestine drug laboratory chemicals. Children of drug producers were considered as bystanders.

Results

Adverse health effects were reported in the case reports/series in 84 individuals, of whom 57 were adults and 27 children. Thirty-four were bystanders from the general public or children of drug producers (27 children and seven adults); 23 (18 male, four unknown) were drug producers, and 27 were first responders. Subjects were exposed to chemicals used in the production of metamfetamine (n = 78), MDMA (n = 3), amfetamine (n = 2) and amfetamine-type drugs (n = 1).

The retrospective surveillance studies covered larger numbers of subjects (40 to 947 injured persons per study). Five of these studies were conducted using data from the United States Hazardous Substances Emergency Events Surveillance (HSEES) system (1990–2009), and its successor the National Toxic Substance Incidents Program (NTSIP) (2009-), focusing on first responders [10] or members of the general public [11–14]. These programs were set up to monitor events involving exposure to harmful chemicals in general, not to monitor drug laboratory incidents per se.

Chemicals involved in clandestine drug laboratory-related exposures could roughly be divided in four groups: irritating gases with systemic effects (phosphine, hydrogen sulfide), solvents (acetone, toluene, methanol), caustic agents (acids, alkalis, oxidizing agents) and sympathomimetic chemicals (Table 1, Supplementary Tables 1 and 2). Exposure to anhydrous ammonia was reported most frequently [10–12,15–19].

Table 1. Chemicals and their routes of exposure as mentioned in case reports and surveillance studies on exposures to chemicals from clandestine drug laboratories.

Chemical	Mode of action	Route of exposure	Reference
Irritating gases with systemic effects
Hydrogen sulfide	Blockage cytochrome c oxidase Neuronal inhibition Local (lung)irritation	Inhalation	[44]
Phosphine	Blockage cytochrome c oxidase (Lung)tissue damage	Inhalation	[20,22,23]
Solvents
Acetone	CNS depressant Local irritation	Inhalation, eye, skin	[35]
Methanol	CNS depressant Neurotoxic Acid/base disturbances Nephrotoxic	Inhalation	[40,41]
Naphta	CNS depressant Neurotoxic Local irritation	Inhalation	[15]
Toluene	CNS depressant Neurotoxic Local irritation	Inhalation, eye, skin	[15]
Solvent (undefined)		Inhalation, eye, skin	[35]
Caustic chemicals
Anhydrous ammonia	Alkaline chemical	Inhalation, eye, skin	[10–12,15–19]
Hydrochloric acid	Acidic chemical	Inhalation, eye, skin	[10,11,35]
Iodine	Oxidizing chemical	Inhalation	[15]
Lye	Alkaline chemical	Eye, skin	[15,17]
Sodium hydroxide	Alkaline chemical	Inhalation, eye, skin	[10,35]
Sulfuric acid	Acidic chemical	Skin, ingestion	[32,33]
Acid (not specified)	Acidic chemical	Inhalation, eye, skin	[35]
Alkali (not specified)	Alkaline chemical	Eye	[17]
CNS stimulating chemicals
Ephedrine	Sympathomimetic	Inhalation	[15]
Metamfetamine	Sympathomimetic	Inhalation, eye, skin, ingestion	[26,39]

Inhalation injuries

In the case reports (Supplementary Table 1), inhalation was the most common route of exposure to drug laboratory chemicals (reported in 52 persons (34 adults, 18 children)). As a consequence, respiratory effects were common in patients exposed to chemicals from clandestine drug laboratories, with 36 (43%) of the 84 described patients experiencing respiratory effects. Effects ranged from respiratory irritation/distress (n = 27, 33%) to dyspnea (n = 12, 15%), cough (n = 6, 7%), respiratory sounds (n = 2, 2%), and lung edema (n = 2, 2%). Among others, anhydrous ammonia and phosphine were reported chemicals involved in drug laboratory-related exposures.

Inhalation of anhydrous ammonia

Anhydrous ammonia inhalation exposure was supposedly involved in 11 patients experiencing respiratory adverse effects [10,11,15,18]. In the cases reported by Horton et al. [15], no data were given about the specific circumstances of exposure in the six children. Cooper et al. [10] described three police officers who suffered respiratory irritation after exposure to anhydrous ammonia and diethyl ether during a raid on a clandestine drug laboratory [10]. No data on exposure concentrations were provided. In another report, a police officer noticed the smell of ammonia on a motorist who had experienced respiratory and eye irritation [11]. The motorist was exposed to chemicals in his home/clandestine drug laboratory, where ammonia, sulfuric acid, sodium hydroxide, and diethyl ether were found.

Inhalation of fumes of any of these substances can result in respiratory irritation, making it difficult to correlate the respiratory problems to the specific inhalation of ammonia. In the case reported by Dhaliwal and Sood [18] an adult metamfetamine producer was exposed to anhydrous ammonia during an explosion in a clandestine laboratory in the basement of his home. Besides skin burns, the patient had difficulty with breathing, wheezing, pharyngeal erythema and thick nasal discharge. There were no further data provided on airborne concentrations of anhydrous ammonia, nor was there any mention of the involvement of thermal effects. In summary, while the reported symptoms match exposure to anhydrous ammonia, exposure was not always clear, with other chemicals involved, or confirmed.

Four retrospective surveillance data analyses also indicate the large proportion of events involving anhydrous ammonia [10–12,19]. The studies by Cooper et al. [10,11] both showed a predominant involvement of anhydrous ammonia (16–33.3%), with 39–54% of all injuries consisting of respiratory irritation. The causes of respiratory irritation were not further specified and exposure to other substances, including hydrochloric acid were mentioned. It was not possible to further derive how many people experienced respiratory irritation due to inhalation of anhydrous ammonia. Arant et al. [12] focused on exposures to anhydrous ammonia, but only on events associated with theft of anhydrous ammonia for use in clandestine drug synthesis, with no actual involvement of exposures in clandestine drug laboratories. Sixty-two percent of the reported injuries consisted of respiratory irritation. Most victims were treated at a hospital but not admitted. No deaths occurred. No mention was made about the concentrations of anhydrous ammonia to which victims were exposed. Bloom et al. [19] described injuries of patients admitted to a hospital due to anhydrous ammonia exposures from incidents during illicit metamfetamine production [19]. All reported patients (n = 15) had “inhalation injury”, which was not further defined. For most patients (14/15), the anhydrous ammonia exposure went together with an explosion. It was unclear to which extent inhalation injuries were due to the anhydrous ammonia.

Inhalation of phosphine

Severe respiratory effects followed exposure to phosphine in three suspected producers found dead in a poorly ventilated clandestine drug laboratory [20]. Deputies noticed a “heavy chemical odor” and measurements near the presumed reaction vessel showed a phosphine concentration of >0.3 ppm, higher than the maximum detection limit of the used analytical method. The Acute Exposure Guideline Levels (AEGLs) Level 3 for 10 min, 1 h and 8 h exposure are 7.2 ppm, 3.6 ppm and 0.45 ppm, respectively. AEGL-3 corresponds to Life-threatening health effects or death [21]. Autopsy of the person closest to the reaction vessel showed pulmonary edema, consistent with the inhalation of high phosphine concentrations. “Phosphine gas toxicity by inhalation” was considered the cause of death for all three victims. There were no methods available for phosphine determination in biological specimen. In another case, two persons were found dead in a clandestine metamfetamine laboratory in a hotel room [22]. Because of the set-up, phosphine exposure was suspected. A phosphine concentration of 0.15 ppm was measured in the room, and when the phosphine concentration in the reaction vessel was measured, the concentration "soared" (not quantified). There was no confirmation by the medical examiner that phosphine exposure was the likely cause of death.

In a third case, a forensic specialist investigating a metamfetamine lab was exposed to phosphine [23]. She worked for 20–30 min in the seized laboratory and noticed a garlic odor. Subsequent measurements showed a phosphine concentration of 2.7 ppm in the work area. She developed dizziness, dry cough, headache, and diarrhea shortly afterwards. In the following days, she developed temporary bilateral rhonchi, persistent cough and dyspnea after exposure. Cough and dyspnea improved slowly, but were still present at reduced level 9 months after exposure. The observed clinical symptoms may be expected at the measured phosphine concentration and duration of exposure. A co-investigator, present in the same area but probably exposed to lower phosphine concentrations, developed similar (undefined) symptoms. No follow-up was available for this patient.

Inhalation of other chemicals

Respiratory features were described after inhalation of (combinations of) undefined chemicals, solvents, acids, whether or not during fires or explosions [15,24,25]. These individuals experienced mild symptoms after being in (former) clandestine drug laboratories or near undefined chemical waste. Moreover, five hospital employees developed respiratory irritation after decontamination of a patient from an illegal metamfetamine laboratory [25]. In all of these cases, the chemicals involved were unknown and there was no measurement of exposure concentrations. The involvement of acids and solvents has been shown in surveillance studies [10,11]. Of all laboratory events causing injuries, 8–30.6% and 13% were related to hydrochloric acid and solvents, respectively. In general, symptoms were restricted to respiratory irritation. It is not clear from these surveillance studies that symptoms were solely attributable to hydrochloric acid or solvents.

Wright et al. [26] reported a family of five who had lived for 1.5 years in a former clandestine drug laboratory. The family vacated their residence due to elevated metamfetamine concentrations, which ranged from 11.7–26.0 μg/100 cm², found on surfaces in the house. Two siblings had developed asthma-like symptoms, another sibling and a parent had developed a persistent cough. Metamfetamine was detected in the hair of all family members, confirming exposure to metamfetamine. The association between asthma-like symptoms and chronic metamfetamine exposure is not clear. Animal studies have been published describing a possible association between asthma exacerbation and long-term amfetamine exposure [27], although a recent study could not find such an association for metamfetamine in humans [28].

Respiratory exposure in surveillance studies

Respiratory adverse effects were observed in several retrospective surveillance studies (Supplementary table 2). In the 5 HSEES/NTSIP studies, the number of respiratory effects were quantified relative to all observed adverse effects in patients. Respiratory irritation (defined as “e.g., cough, difficulty breathing, and throat irritation”) covered 39-62% of all observed symptoms in these studies [10–14]. The reports did not discuss causal relationships between exposures and symptoms.

Three studies focused on adverse effects in law enforcement personnel investigating clandestine drug laboratories [29–31]. Self-reported effects experienced after (repeated) investigations included sore throat, cough, wheezing, dyspnea, bronchitis, pneumonia, emphysema, decreased pulmonary function and lung damage. In general, symptoms were mild and short-term, but occasionally long-term respiratory effects were observed. Adverse effects were greater in personnel investigating active rather than inactive laboratories. In all three studies, the chemicals involved were not identified.

Overall, according to the surveillance studies, 59% of those who were exposed to drug laboratory chemicals developed respiratory adverse effects (Table 2).

Table 2. Frequencies of symptoms observed in surveillance studies of exposures to chemicals from drug laboratories.

		respiratory														skin		eye			gastrointestinal				systemic				chemicals involved
Reference	number of subjects	irritation	dyspnea	throat irritation	cough	nasal irritation	chest pain	lung damage	injury	wheezing	chest cold	bronchitis	pneumonia	emphysema	respiratory symptoms	irritation	burns	irritation	burns	injury	nausea	vomitting	abdominal pain	gastrointestinal problems	dizzines /cns	headache	tachycardia	dead
Cooper et al. [10]	155	60	10													1	3	12			9				10	3			anhydrous ammonia, hydrochloric acid, sodium hydroxide
Cooper et al. [11]	947	531																109	104							348		9	ammonia (16% of meth events), meth chemicals (not otherwise specified, 13%) hydrochloric acid (8%)
Arant et al. [12]	85	68																19											anhydrous ammonia
Melnikova et al. [13]	902	485	18													32		99	139					75	67	307		18	not specified
Melnikova et al. [14]	162								72							17	44	35						11	9	11		2	not specified
Bloom et al. [19]	15								15											10									anhydrous ammonia
Thrasher et al. [24]	198		36	40	24	21										15		39	7		52				22	70			ammonia, methamfetamine
Burgess et al. [29]	59		4	12	7	8	2	1								3		3			1		2		3	12			not specified
Burgess et al. [30]	40		6		5					6	4	3	3	1															not specified
Witter et al. [30]	240			95			18								102	59				71				22	76	131	19		not specified
sum	2803	1144	74	147	36	29	20	1	87	6	4	3	3	1	102	127	47	316	250	81	62	0	2	108	187	882	19	29
total per respiratory, skin, eye, gastrointestinal, systemic or dead		1657 59%														174 6%		647 23%			172 6%					1088 39%		29 1%

Conclusion: inhalation

Respiratory symptoms were observed frequently in those exposed to chemicals present in clandestine drug laboratories. Respiratory symptoms were generally mild, with cough and respiratory irritation. Occasionally, more severe symptoms, such as lung edema, were observed. Long-term or repeated exposure to low concentrations of residual chemicals in former laboratories, was associated with respiratory effects, including persistent cough and asthma-like symptoms. Respiratory effects were usually related to inhalation of alkali (mostly anhydrous ammonia), acids (mostly hydrochloric acid) and solvents. Severe adverse effects were observed after the inhalation of accidentally released phosphine.

Skin exposure

Skin exposure was the second most common route of exposure observed in the reported cases (27 persons (16 adults, 11 children), see Supplementary Table 1). Hence, dermal symptoms were among the most prevalent symptoms observed after exposure to chemicals from clandestine drug laboratories. Dermal symptoms were observed in 25 patients (30%), consisting of chemical burns (n = 14, 17%), skin irritation (n = 10, 12%), burning sensation (n = 1, 1%) and rash (n = 1, 1%).

Skin exposure to anhydrous ammonia

Anhydrous ammonia was involved in eight patients displaying dermal symptoms [12,15,16,18]. Three of these patients were children exposed during the “spill/volatilization” of anhydrous ammonia during one metamfetamine-related event resulting in “skin irritation” [15]. No further details regarding exposure concentration, exposure duration and time of onset of symptoms were given. Lee et al. [16] discussed three producers who admitted to being exposed to anhydrous ammonia during metamfetamine production. All three had second degree facial burns and ocular chemical burns. At least for one of the patients an explosion was involved, suggesting that the facial and ocular burns could have been caused by heat as well. Arant et al. [12] described a producer who sustained chemical burns after accidental exposure during the theft of anhydrous ammonia. The patient was taken to an emergency department. Dhaliwal and Sood [18] reported on a patient supposedly exposed to anhydrous ammonia during an explosion in a clandestine metamfetamine laboratory. He had second-degree skin burns on face, neck and hands. It was not described to what extent the burns were the result of thermal exposure.

The frequent involvement of anhydrous ammonia in adverse dermal effects was further emphasized by Bloom et al. [19] who reviewed the medical records of patients admitted to a tertiary hospital with a specialized burn unit. Fifteen people were injured in clandestine drug laboratory accidents involving anhydrous ammonia. Injury was caused by chemical exposure alone (n = 1), thermal exposure alone (n = 2), or a combination of both (n = 12). On average, 20.5% of the body surface was burned in these cases.

Skin exposure to sulfuric acid

In three cases skin burns were observed after exposure to sulfuric acid [32,33]. Three children (1, 2 and 5 years) accidentally drank drain opener containing 95% sulfuric acid. The drain openers were used for metamfetamine production in their parents’ homes. Besides severe gastrointestinal burns (see below), second-degree skin burns of the hands, neck, chest and abdomen also resulted from exposure. The youngest child died approximately one hour after ingestion due to gastrointestinal injury.

Skin exposure to other chemicals

Horton et al. [25] described a number of people who developed adverse dermal effects after the exposure to a combination of unknown chemicals after explosions. Two producers developed chemical burns after the explosion of an oven while using a mixture of acetone, hydrochloric acid and sodium hydroxide. It was not clear whether the burns were due to heat, chemicals or a combination of both. Another producer sustained burns over 15% of his body after an explosion and fire in his apartment which was used as a clandestine drug laboratory. He was using at least 5 gallons of various acids and solvent. The nature of the skin burns was not described further. During this incident four members of the general public and two emergency medical technicians developed skin irritation, but circumstances of exposure were not given.

Manning [34] described two children who suffered second-degree chemical burns on their arms after they had fallen in clandestine drug laboratory waste dumped by their parents.

Thrasher et al. [24] reported two persons who developed mild adverse dermal effects after exposure to unknown chemicals. An 18-year-old male had a burning sensation on his hand while cleaning up after a fire in a clandestine drug laboratory, suggesting exposure to an irritating or caustic substance. A 15-year-old producer developed flushing after an unknown chemical was spilled onto his skin. This person also developed agitation, suggesting that the observed symptoms were caused by systemic toxicity after skin absorption. Another option would be that these symptoms were related to his abuse of metamfetamine, since agitation and flushing are both reported as adverse effects of metamfetamine use.

Skin exposure in surveillance studies

Dermal symptoms were described in several retrospective surveillance studies (Supplementary Table 2), with 6% overall of those exposed having skin irritation and/or skin burns (Table 2). Specific numbers regarding the frequency of skin irritation and burns were difficult to obtain from these studies, since often no clear distinction between skin irritation, chemical skin burn or thermal burn was made. Cooper et al. [10] described the occurrence of chemical burns in 4% of the first responders (firemen) injured at clandestine drug laboratory incidents; only one emergency medical technician (1% of all first responders included in the study) had skin irritation.

In another study, Cooper et al. [11] reported that 11% of the injured people, first responders or members of the public, had skin burns. No distinction was made between chemical, thermal or combined burns. The predominant chemicals involved in both studies were anhydrous ammonia, hydrochloric acid and (unspecified) solvents, but the contribution of these substances in the development of adverse dermal effects was not clear.

Witter et al. [31] stated that dermal symptoms were observed in 25% of law enforcement personnel involved in clandestine drug investigations, and symptoms ranged from rash to burns. Medical treatment was sought by 17% of the respondents with skin injury, and the median duration of symptoms was 6 h (range 0.02-2160 h). In 22% of the respondents with skin injury symptoms lasted >24 h. The use of personal protection equipment was associated with less dermal symptoms. The identity of involved chemicals was not addressed in this study.

Thrasher et al. [24] compared dermal symptoms between different exposure groups [24]. Strikingly, dermal effects occurred frequently among drug producers, with 48% of all the reported drug producers experiencing skin irritation or skin burns.

Moreover, drug producers were the only exposure group with skin burns, with 57% being chemical burns and 43% thermal burns. Skin irritation was observed in 3%, 11% and 11% of exposed law enforcement personnel, bystanders and children, respectively. These data suggest that producers are at higher risk for severe dermal effects than first responders and bystanders.

Finally, the symptom frequency of dermal injury among people injured in metamfetamine laboratory events was analyzed in two studies by Melnikova et al. [13,14]. In the first study, chemical burns, skin irritation and thermal burns were found in 15, 4 and 3% of all victims of drug laboratory incidents [13]. The second study showed that 27% of all reported victims of drug laboratory incidents (n = 162) had burns, without specification of chemical or thermal burns, and 10% had skin irritation [14]. The frequency of burn was highest among members of the general public, with 43% of the observed injuries in this population being burns. Adverse effects experienced by producers were not included in this study. Both studies [13,14] did not elaborate on the identity of involved chemicals causing the adverse effects.

Conclusion: skin exposure

Dermal adverse effects were reported after exposure to chemicals found in clandestine drug laboratories. Effects ranged from skin irritation to severe burns. Alkaline chemicals, predominantly anhydrous ammonia, acids and solvents were usually involved. Often burns were caused by a combination of chemical exposure and thermal effects. Adverse dermal effects have been reported in drug producers, first responders/law enforcement personnel and bystanders. Small children living in houses serving as clandestine drug laboratories are at risk for severe caustic burns due to the presence of highly concentrated caustic substances to which they may be exposed to accidentally.

Eye exposure

In 35% (n = 29) of the 84 included cases (Supplementary Table 1), ocular adverse events were reported, most of which were attributable to eye exposure. Frequently described ocular symptoms were irritation (n = 16, 20%), lacrimation (n = 6, 7%), corneal damage (n = 4, 5%), chemical burns (n = 3, 4%), photophobia (n = 2, 2%) and decreased vision (n = 3, 4%). Ocular irritation was predominantly described when victims were exposed to corrosive or irritating gasses (anhydrous ammonia and other alkaline chemicals, acids, solvents) [11,15,35]. Ocular irritation was usually accompanied by respiratory irritation. As indicated previously, the information regarding exposure circumstances was limited for most of these reported cases.

Severe eye damage was observed after explosions during the synthesis of metamfetamine [16]. Based on statements from the victims, it was assumed that it concerned exposure to anhydrous ammonia. The three producers displayed grade I–III ocular burns, ocular pain and photophobia. These symptoms are in accordance with exposure to high concentrations of anhydrous ammonia [36]. Ocular injury due to exposure to anhydrous ammonia, whether or not combined with heat, was also shown by the aforementioned study by Bloom et al. [19], which did not elaborate further on the severity of ocular symptoms.

Four cases of severe ocular burns were described after exposure to alkaline reaction mixtures which were released during failed “one-pot” metamfetamine synthesis [17]. The observed adverse ocular effects were severe and caused by both caustic and thermal effects. Symptoms included corneal damage, conjunctivitis, glaucoma, limbal and conjunctival ischemia and conjunctival necrosis. None of the patients initially informed their physicians that they were exposed during metamfetamine synthesis. However, based on the suspicion that the patients abused metamfetamine, alkali exposure was assumed. In one patient, the pH of the eye was 11 at time of admission.

Less severe ocular effects were observed in a patient involved in an explosion in a clandestine metamfetamine laboratory which allegedly resulted in anhydrous ammonia exposure [18]. The patient had vision loss, conjunctival erythema and lacrimation. Mild adverse ocular effects were observed in the previously mentioned family residing in a former clandestine drug laboratory [26]. All five family members developed sore, watery eyes, but the time of onset was not given. Sore, watery eyes suggest exposure to irritant gasses, but this was not confirmed in the article. Both parents showed additional ocular effects (blurry vision and improved distance vision) which suggest systemic effects caused by metamfetamine. However, the found hair concentration of metamfetamine was not conclusive to make such statement.

The retrospective surveillance studies included in this review mainly reported “eye irritation” as adverse ocular effect, without further clarification. Eye irritation was experienced by 11–42% of the reported victims [10–14,24,29], with the highest incidence of eye irritation among law enforcement personnel exposed to chemicals from metamfetamine laboratories [24].

In the study of Witter et al. [31], 30% of law enforcement personnel experienced adverse ocular effects after clandestine drug laboratory investigations (ocular pain or vision problems), but exact ocular symptoms were not further specified. For all of these studies, the exact nature of the chemicals involved was not addressed.

Conclusion-eye exposure

In conclusion, ocular irritation is frequently described after exposure to chemicals from clandestine drug laboratories, mostly due to exposure to corrosive or irritating gasses. Severe cases of ocular injury were seen after direct eye contact with alkaline reaction mixtures, especially after explosions of reaction vessels.

Ingestion

In six reported cases (Supplementary Table 1), there was clear evidence of ingestion. In case of the aforementioned family living in a former drug laboratory [26], ingestion was assumed. Gastrointestinal symptoms were observed six times after ingestion. In 5% (n = 4) of the included cases, severe gastrointestinal adverse effects were observed after ingestion of caustic agents used in clandestine drug synthesis [32,33,37].

The three previously mentioned children who drank drain cleaner containing sulfuric acid used in the synthesis of metamfetamine, developed severe chemical burns in the upper gastrointestinal tract [32,33]. The first, a 5-year-old boy, had burned lips, tongue, oropharynx, uvula, bilateral tonsils, epiglottis, false and true vocal chords and arytenoids. He developed edema of the oropharynx, esophagitis and gastritis. Blood gas analysis showed a metabolic acidosis (pH 7.26, bicarbonate concentration 13.7 mmol/L). He was discharged 2 months after admission, with subsequent requirement of esophageal resection and replacement due to stricture formation [32]. The second child, a 2-year-old boy, had burns to the lips and anterior oral cavity. Further examination showed injury in the posterior pharynx. Blood gas analysis showed metabolic acidosis (pH 7.27, bicarbonate concentration 14.6 mmol/L). An esophageal stricture was observed 7 days after admission, requiring esophageal dilatation [32]. The third child was a 1-year-old boy who developed bradycardia and died shortly after admission. Postmortem analysis showed mural perforation of the distal esophagus with complete separation of the stomach from the esophagus. Extensive corrosive changes in the upper gastrointestinal tract were observed. Moreover, gastric content was aspired in the lungs and pulmonary edema was observed [33].

Chahid et al. [37] described an adult drug producer, who, in the context of a bet, drank a liquid used in the synthesis of amfetamine. He vomited shortly after and presented in the hospital with caustic damage of the distal esophagus and cardia. Gastric contents retrieved during gastric lavage had a pH of 9, showing that the ingested fluid was alkaline.

Retrospective surveillance data showed that gastrointestinal effects were observed overall in 6% of those exposed (Table 2) [10,13,14,24,29,31]. The highest incidence was reported among law enforcement personnel being exposed to drug laboratory chemicals [24]. Gastrointestinal symptoms were specified as “gastrointestinal” or “gastrointestinal problems” [13,14], “nausea/vomiting, diarrhea, abdominal pain or no appetite” [31], “abdominal pain” or “nausea” [29] and “nausea/vomiting” [10,24]. No statements were given in any of the articles about the chemicals involved in gastrointestinal symptoms, or their route of exposure.

Conclusion: ingestion

In conclusion, gastrointestinal adverse effects after exposures to chemicals from clandestine drug laboratories are less common than respiratory, dermal and ocular effects. Adverse effects are generally restricted to mild symptoms like nausea and vomiting. Ingestion of caustic chemicals involved in drug synthesis can lead to severe gastrointestinal burns, possibly leading to death.

Systemic effects

Most of the aforementioned respiratory, dermal, ocular and gastrointestinal symptoms reported in the different cases/studies were local adverse effects, due to direct contact of chemicals with tissue. In a number of cases systemic effects were also reported. The most common systemic effects were headache and dizziness, which were observed in respectively 15% and 5% of the reported cases (Supplementary Table 1). In case of the surveillance studies (Supplementary Table 2) headache and dizziness accounted for respectively 3–60% and 7–15% of all observed symptoms [10,11,13,14,24,29].

In a few cases, sympathomimetic effects were observed after exposure to chemicals from clandestine drug laboratories. Sympathomimetic overstimulation is characterized by specific cardiovascular and neurological symptoms [38]. A man with a history of metamfetamine abuse developed sympathomimetic symptoms after making coffee with a filter previously used for metamfetamine synthesis [39]. Within hours he developed hyperthermia (42.2 °C), tachycardia (180 bpm), wide complex rhythm, hypotension (74/28 mm Hg), muscle rigidity and metabolic acidosis (pH 7.23, bicarbonate concentration 10.7 mmol/L). He was treated in a hospital with medicinal intervention and aggressive cooling. A urine toxicology screen was positive for high concentrations of amfetamine (not quantified), highly suggestive that the patient was suffering from metamfetamine poisoning.

Chahid et al. [37] described another two patients admitted with signs of sympathomimetic toxicity. A 14-year-old girl accidentally ingested a sip of fluid from a bottle prepared by her father, probably containing precursor chemicals for the synthesis of amfetamine-type stimulants. She developed mydriasis, general hypertonia, convulsions, cyanosis, respiratory depression, bradycardia (30 bpm) and pulseless electrical activity. After resuscitation (with heart massage and the use of atropine), she had a tachycardia (150 bpm) and heart ischemia with severe ST depression in all leads. Blood analysis showed a combined respiratory and metabolic acidosis (pH 7.12, pCO₂ 61.5 mm Hg [8.2 kPa], bicarbonate concentration 17 mmol/L, base excess −9.9 mmol/L, lactate concentration 9.7 mmol/L). Her heart rate dropped to 122 bpm, with a blood pressure of 80/45 mm Hg. During her 12 h stay at the intensive care unit, the hemodynamic and neurological symptoms normalized. Toxicology screens for urine and blood were both positive for amfetamines. Subsequent analysis of the content of the bottle showed the presence of a mixture of drug precursors and amfetamine-type stimulants, explaining the observed clinical symptoms. Respiratory depression and bradycardia are atypical symptoms which have been observed with amfetamine-type stimulants in rare occasions [39].

The second patient was a drug producer, who drank a liquid used in the synthesis of amfetamine [37]. Half an hour later, he presented to the hospital with sympathomimetic symptoms (mydriasis, tremor, hypertension (168/80 mmHg), tachycardia (124 bpm), palpitations) and caustic damage of the distal esophagus and cardia. No blood acid-base disturbances were observed and no further toxicological analysis of blood or urine were performed. The notion that the liquid was used for amfetamine synthesis, together with the observed sympathomimetic symptoms, suggested the presence of amfetamine-type stimulants in the liquid.

The previously described family residing in a former metamfetamine laboratory also displayed mild symptoms reminiscent of amfetamine-type stimulation [26]. Laboratory analysis showed the presence of metamfetamine in the hair of all family members (concentrations: 5-460 pg metamfetamine/mg hair, one week after vacating their home), with the youngest son having the highest concentration. This 7-year-old boy experienced sleeping problems with vivid/scary dreaming, irritability, somatization and Attention Deficit Hyperactivity Disorder (not present before moving into the formal drug laboratory). His 8-year-old brother did not show symptoms shortly after vacating the formal drug laboratory, but experienced anxiety and somatization 3 months after vacating home. Their 11-year-old sister had trouble sleeping and was irritable during her stay in the residence. The 40-year-old mother experienced an excess of energy, weight loss and improved distance vision, while the 38-year-old father experienced sleeping problems and decreased memory function. During cleaning of contaminated areas, he experienced dizziness and blurry vision. For all family members, the symptoms resolved during the 6-12 months after leaving the contaminated house.

Wijnands-Kleukers et al. [40,41] described three cases of methanol poisoning during the synthesis of MDMA. Three drug producers were admitted to the hospital with clear symptoms of toxic alcohol poisoning. The first patient was unresponsive (Glasgow Coma Scale (GCS) 3), had apnea, hypertension (blood pressure 166/78 mm Hg), tachycardia (129 bpm), and fixed dilated pupils. He had a severe metabolic acidosis (pH 6.31, bicarbonate 4 mmol/L) with increased anion gap (46.9 mmol/L), increased lactate (21.7 mmol/L) and an increased osmolal gap (108 mmol/L). The highest measured methanol serum concentration was 1.6 g/L (50 mmol/L). The patient died after 4 days due to progressive multiorgan failure and massive cerebral edema, despite hemodialysis and treatment with ethanol/fomepizole and folinic acid. The second and third patient entered the hospital with GCS score 14 and 15, respectively. They both had metabolic acidosis (pH 7.1, bicarbonate concentration 4 mmol/L; pH 7.2, bicarbonate concentration 5 mmol/L, respectively), increased anion gap (39.6 mmol/L and 22 mmol/L, respectively) and osmolal gap (54 mmol/L and 41 mmol/L, respectively). The highest measured serum methanol concentrations were 1.1 g/L (34 mmol/L) and 0.9 g/L (28 mmol/L), respectively. Both patients recovered within 4 days after hemodialysis, ethanol/fomepizole treatment and folinic acid supplementation. It appeared that the drug producers worked in a poorly ventilated clandestine drug laboratory for more than 40 consecutive hours, suggesting methanol poisoning following inhalation of high concentrations of methanol.

Gastrointestinal symptoms were observed in a few cases after inhalation exposure to different chemicals. Such symptoms can be considered systemic, since they are not the result of local effects in the gastrointestinal tract. Diarrhea was observed shortly after a forensic specialist was exposed to phosphine gas [23]. Nausea and vomiting were reported in emergency department personnel who decontaminated a producer of metamfetamine with chemical burns [35]. The producer was probably exposed to a mixture of acetone, hydrochloric acid and sodium hydroxide after explosion of a reaction vessel. Exposure to such chemicals may result in nausea and vomiting, as solvents are known to cause gastrointestinal discomfort when inhaled [42].

The main systemic effects reported in the retrospective surveillance studies were headache and dizziness. Headache was overall reported in 34% of those exposed (Table 2) [10,11,13,14,24,29,31]. The incidence of headache was high (55–60%), predominantly among law enforcement personnel and laboratory investigators occupationally exposed [24,29,31], whereas dizziness or mild, usually undefined, effects on the central nervous system (CNS) occurred in 7% overall (Table 2) [10,13,14,19,24].

Witter et al. [31] reported a high incidence of 32% of CNS effects among law enforcement personnel involved in metamfetamine laboratory investigations. Symptoms that were classified as CNS effects were dizziness, seizures, loss of consciousness, tremors, drowsiness, lightheadedness, confusion, anxiety, slurred speech or agitation. The incidence of each separate symptom was not given. In addition, 8% of the law enforcement personnel reported increased heart rate.

Conclusion: systemic effects

In conclusion, systemic adverse effects after exposure to chemicals present in clandestine drug laboratories are usually restricted to mild symptoms like headache or dizziness. Law enforcement personnel may suffer more frequently from these symptoms. Severe systemic effects can occur upon exposure to specific substances, such as toxic alcohols or amfetamine-type stimulants, under specific circumstances.

Fatalities

In the cases in this review (Supplementary Table 1), six patients (7%) died after exposure to chemicals from clandestine drug laboratories. Five previously discussed patients who were found dead in a clandestine drug laboratory, most likely died after phosphine inhalation [20, 22]. Causes of death after phosphine exposure usually involved circulatory failure [43].

Another fatal case involved exposure to hydrogen sulfide [44]. A drug producer, found dead in an active metamfetamine laboratory, probably had mistaken hydrogen sulfide for hydrochloric acid to salt out the end product. The hydrogen sulfide gas cylinder was freely discharging when the victim was found by first responders. Exposure to high concentrations of hydrogen sulfide can cause a “knock-down” with seizures, coma, cardiovascular collapse and respiratory failure and death [45]. Hydrogen sulfide concentrations in the air or in biological material of the deceased were not determined, suggesting that other causes of death could not be excluded.

In the aforementioned case of a 1-year-old boy ingesting sulfuric acid, the child developed bradycardia shortly after arrival at the emergency department. Subsequent resuscitation was in vain. Autopsy revealed severe gastrointestinal damage (including esophageal perforation and complete separation of the stomach from the oesophagus) and lung oedema due to aspiration of sulfuric acid.

Finally, a drug producer died in the hospital after prolonged exposure to high concentrations of methanol vapour [40]. The patient was found unresponsive with a severe metabolic lactate acidosis and high anion gap, and died of progressive multiorgan failure and massive cerebral oedema. High concentrations of methanol were measured in serum (1.6 g/L), making methanol poisoning a plausible cause of death [41].

With respect to the retrospective surveillance studies (Supplementary Table 2), only three studies reported fatalities. Approximately 1% of the victims of metamfetamine laboratory events died [11,13,14]. Causes of death were not given, except for the case in which a drug producer died of thermal injury [11].

Melnikova et al. [13] reported 18 people who died; 13 deaths occurred in clandestine drug laboratories or on arrival at hospital, three deaths occurred after arrival at hospital, and two deaths occurred at unknown times. In the other study by Melnokiva et al. [14], two fatalities were mentioned: a drug producer and a law enforcement officer. For all these fatalities it was unclear if chemical exposure were the cause of death, or thermal injury or trauma were involved.

Conclusion: fatalities

In conclusion, fatalities after exposure to chemicals from clandestine drug laboratories have been reported occasionally. Retrospective analysis showed that about 1% of metamfetamine laboratory-related victims died. Causes of death were usually not given and could have included thermal effects and trauma. In the overview of cases 10% of 84 victims died, but fatalities could be overrepresented due to publication bias.

Limitations

Despite the large amounts of illicit drugs produced globally and the vast number of clandestine drug laboratories in the world, the number of cases described with adverse health effects after exposure to clandestine drug laboratory chemicals is limited (n = 84, from 1999 till 2021). Moreover, several of these case descriptions present limited information regarding the circumstances of exposure and the clinical symptoms. Since the surveillance data suggest that exposure to chemicals from clandestine drug laboratories occur frequently, the low number of reported cases may have different explanations.

On the one hand, publication bias may be involved, especially when taking into account that the identity of the involved clandestine drug laboratory chemical is often unknown and most of the victims will probably have relative mild symptoms. On the other hand, drug producers may not present readily to hospital after a laboratory exposure, although the study by Thrasher et al. [24] suggested a high rate of hospitalization for drug producers and the number of drug producers in the study was considerable (23 drug producers/84 subjects). Moreover, drug producers might not always disclose that they were injured in a drug laboratory related incident.

Since clandestine drug synthesis is a worldwide phenomenon, it is remarkable that most of the cases and surveillance studies taken up in this overview were from the United States. Several explanations can be given for this finding. First, drug abuse is relatively common in the United States compared to other countries [46]. Second, the United States are the largest publisher of biomedical literature in the world [47], which may cause a publication bias with regard to the origin of publication. Third, the HSEES/NTSIP surveillance systems enable the study of clandestine drug laboratory related exposures. Five out of ten of the studies analyzed in this review originated from the HSEES program [10–14]. Three case reports found their origin in retrospective analysis of HSEES data [15,25,35]. Since amfetamine type of drugs are also produced in large scale in other parts of the world, including Asia, Europe and Oceania [1], it is likely that similar observations can be expected there, although no systematic data are available.

Conclusions

The most common reported adverse effects after exposure to chemicals from clandestine drug laboratories were respiratory, dermal and ocular effects. In general, effects were limited to irritation. The adverse effects were usually caused by exposure to irritating or caustic substances, including solvents, acids or alkaline chemicals. Anhydrous ammonia was one of the most commonly involved chemicals and serious adverse effects were reported after exposure to phosphine, hydrogen sulfide, methanol and highly concentrated acids and alkaline chemicals. Effects can occur locally or systemically or as a combination of both. Fatalities have been estimated to occur in 1% of the patients injured in clandestine drug laboratory events. It is unclear to what extent chemical exposure contributed directly to this mortality rate.

Acknowledgement

The authors thank Professor Allister Vale for his invaluable contribution to improve this review.

Disclosure statement

Arjen Koppen, Anja Wijnands-Kleukers, Femke Gresnigt and Dylan de Lange declare that they have no conflict of interest.