Alopecia and Associated Toxic Agents: A Systematic Review

Importance/Objective: There are a number of toxic agents that can cause alopecia. In this review we summarize the known substances that cause alopecia as one of the clinical signs of overdose or toxicity. Evidence Review: A search was conducted using PubMed, EMBASE, and Cochrane for studies describing hair loss of any type as a result of exposure to or ingestion of a toxic agent. The search yielded 856 articles, with 47 studies included in this review. Findings: Agents with the strongest evidence of association to alopecia include thallium, mercury, selenium, and colchicine. Agents with described incidents include boric acid, arsenic, vitamin A, botulinum toxin, Podostroma cornu-damae, and the synthetic opioid MT-45. Conclusions and Relevance: Numerous toxic agents have been implicated in alopecia, and the strength of evidence behind each agent varies. Toxic levels of thallium and colchicine have long been established to cause alopecia, as compared to agents such as botulinum toxin A and synthetic recreational drugs which have less literature describing their links to alopecia and will need further investigation to characterize their relationships to hair loss. Knowledge of typical presentations of hair loss will aid in the development of a differential diagnosis for patients presenting with alopecia.


Introduction
Historically, the literature linking the overdose of certain toxins to hair loss has been heavily focused on heavy metals. In the last decade, the literature still discusses heavy metals, such as thallium and mercury, but now also includes a number of non-metal toxins that are also associated with alopecia. These toxins range from dietary supplements, such as selenium, to prescription drugs, such as colchicine, to fungi, such as Podostroma cornu-damae. In the first review of its kind, we evaluate the evidence behind toxic causes of alopecia and summarize common presentations, as well as associated signs and symptoms of toxicity. Recognition of toxic agents as a possible cause of alopecia, awareness of onset and characteristic patterns of hair loss, and familiarity with common clinical signs will aid in a clinician's differential diagnosis.
Alopecia is the loss of hair from areas of the body where hair would normally grow, which may occur via The search yielded 856 articles. Of those, 47 articles from PubMed and EMBASE remained after filtering for relevancy and exclusion criteria, with no relevant articles from Cochrane. The remaining articles consisted of 5 reviews, 1 patient handout, 1 case-control study, 1 crosssectional observational study, 19 case series, and 20 case reports published between 2007 and 2017. The toxic agents found to be associated with alopecia included: 39   thallium, mercury, selenium, colchicine, boric acid, arsenic, vitamin A, botulinum toxin, Podostroma cornudamae, and the synthetic opioid MT-45 (Table 1). We will discuss the aforementioned toxins in order of decreasing evidence and frequency of reported toxicity.

Thallium
Thallium is a heavy metal whose salt form is tasteless, odorless, colorless, and dissolves completely in liquids. These properties have made thallium an ideal choice for criminal poisonings. The estimated half-life of thallium in humans ranges widely from 1 to 30 days, depending on the dose of thallium [2]. The average lethal dose for thallium sulfate has been reported as 10-15 mg/kg [3]. Polyneuropathy and gastrointestinal symptoms such as diarrhea, nausea, and vomiting are the hallmark symptoms of thallium poisoning, as well as the presence of Mees' lines roughly 1 month after poisoning [4][5][6][7][8].
Thallium was widely used as a rodenticide and insecticide until it was banned in the US in 1972 due to environmental concerns and extreme toxicity [4]. However, cases of both accidental and intentional (malicious or suicidal) poisoning continue to be reported worldwide. Common occupational exposure occurs due to thallium use in the manufacture of certain electronics, semiconductor materials, and alloys [9].
Thallium reportedly causes hair loss by binding to the sulphydryl group of hair keratins, thus disrupting formation of the hair shaft [10]. Thallium poisoning specifically results in anagen effluvium, defined as active hair loss >100 hairs/day over a period of 2-4 weeks, often presenting as diffuse alopecia 2-3 weeks after toxic thallium exposure (Fig. 2). Less commonly, hair loss following thallium exposure may occur over a shorter time course. For example, Li et al. [5] reported the start of hair loss in a 49-year-old female 7 days after the onset of polyneuropathy following malicious thallium poisoning. Namba et al. [11] also reported hair loss 1 week after the ingestion of thallium in 3 out of 5 patients. In addition to anagen effluvium, thallium toxicity can supposedly cause ciliary madarosis, although the authors found no cases reporting the loss of eyelashes [12,13]. However, 4 cases reported loss of eyebrows in thallium-poisoned patients, as well as scalp alopecia [4,6,7,14]. With the exception of 3 case reports, body hair, such as axillary and pubic hair, was spared or not noted [2,7,15].
Thallium and other heavy metals have been added to black market opiates by drug dealers as a way to surreptitiously increase the product weight. Cases of suspected thallium poisoning in heroin users have been reported [16]. In a case-control study by Ghaderi et al. [17], 20 out of 100 patients using street opiates had detectable levels of thallium in their urine, with 45 patients reporting scalp hair loss.

Mercury
Mercury is another heavy metal implicated in alopecia; like thallium, mercury binds to the sulphydryl group of keratins in hair and can result in anagen effluvium [10]. At toxic levels, mercury causes free-radical damage, resulting in symptoms such as fatigue, depression, insomnia, irritability, memory loss, recurrent infections, tremors, and hair loss [18]. French et al. [19] reported a case of a 39-year-old female who intentionally injected herself subcutaneously with mercury to obtain worker's compensation benefits, presenting with rash, hair loss, myalgias, and photosensitivity. Given this patient's presentation, it is unclear whether her symptoms were fictional or influenced by her objective to pursue worker's compensation. Wu et al. [20] described a 51-year-old man presenting with hair loss, fever, dizziness, rash, anorexia, and weakness of extremities after using a topical homeopathic traditional Chinese mineral mixture to treat anal fistulas; analysis of this mixture revealed that it contained mercury and arsenic.

Arsenic
Arsenic is a metalloid naturally occurring in soil, water, and seafood, and used industrially in pesticides, animal feed additives, and metal alloys. The link between Diffuse alopecia from thallium poisoning in a young boy [2]. This is a case of diffuse alopecia following ingestion of an unknown amount of thallium via malicious poisoning. A summary of all included articles [2, 4-8, 10-15, 17-31, 33, 37, 41-43, 51, 52, 56, 64-74]  arsenic and alopecia is not as well delineated as with heavy metals. A cross-sectional observational study performed in West Bengal reported that alopecia was present in 8 out of 73 individuals consuming water containing ≥50 μg/L of arsenic; analysis of the hair and nails revealed arsenic levels of >0.6 μg/L. Skin and mucosal lesions, as well as hepatomegaly, were more frequently reported symptoms [21]. Arsenic has also been reported to cause ciliary madarosis. A 20-year-old female from a South Bengal village with confirmed chronic arsenicosis was reported to have symptoms including xerostomia, xeropthalmia, conjunctivitis, pyogenic skin lesions, palmar-plantar hyperkeratosis, dental caries, and chronic alopecia since childhood (including body hair, eyebrows, and eyelashes) [22]. Seaweed may also contain potentially toxic levels of arsenic. Tandon and Infeld [23] described a case of a 54-year-old female presenting with alopecia, weakness, weight loss, scaly erythematous skin, and nail changes. Her diet consisted mainly of seaweed soup, with the seaweed containing 83.4 mg/L of arsenic, 8,000 times the Environmental Protection Agency's (EPA's) designated safe levels. Her urine arsenic level was >200 µg/g creatinine (Cr), with the reference range <50 µg/g Cr [23]. Amster et al. [24] described a similar case of a 54-year-old female with alopecia starting a few months after beginning kelp supplements. Other symptoms included memory loss, rash, fatigue, nausea, vomiting, and diarrhea; her urine arsenic level was 83.6 µg/g Cr [24] Boric Acid Boric acid, or hydrogen borate, is the weak acid of boron found ubiquitously in nature and used by the enamel, glass, and metal industries [25]. It is also found in insecticides, food preservatives, antiseptics, and flame retardants. Current research reports that boric acid toxicity causes anagen effluvium and eyelash loss [10,12]. In a separate case report, a 56-year-old male presented with alopecia totalis after intentionally ingesting roach killer containing boric acid. Other symptoms included fever, altered mental status, stiffness, diffuse erythematous skin eruption, and bilateral palmar erythema [25].

Selenium
Although selenium is characterized as a non-metal, the symptoms of selenium toxicity can resemble that of heavy metal poisoning, including hair loss and Mees' lines [26]. Other symptoms from acute selenium poisoning include nausea, vomiting, diarrhea, and progression to neurological problems such as unsteady gait and paralysis [27]. A proposed mechanism for the dermatologi- cal symptoms of selenosis involves selenium substituting for sulfur in keratin proteins, thus leading to the loss of disulfide bridges, and abnormal development of hair and nail protein structure [26] Of the 7 case reports or series of selenosis resulting in alopecia included in this review, 5 resulted from the patients' intake of dietary supplements containing selenium, 1 resulted from ingestion of Lecythis ollaria (paradise nuts), and 1 after ingestion from an unknown source. MacFarquhar et al. [28] described a case in which a dietary supplement company misformulated one of their supplements containing selenium. The supplement contained 700 times the recommended daily allowance (RDA), resulting in 201 confirmed cases of adverse events, with 140 patients reporting hair loss [28]. In a case series of patients taking selenium (n = 9), 4 patients developed hair loss within the first week, and eventually, all patients experienced hair loss and 2 patients had alopecia universalis. Symptoms also included diarrhea, myalgia, fatigue, and nail changes [29]. Dosary et al. [30] described another 8 patients who took selenium, who experienced alopecia as early as 1 week. Agarwal et al. [31] described the patchy hair loss, most pronounced in the occipital area, in a patient with selenosis from an unknown source (Fig. 3).
Selenium is also found in high concentrations in Lecythis ollaria nuts (paradise nuts) as seleno-cystathionine; the concentration of selenium can be as high as 7-12 g/kg of dried nuts [32]. Müller and Desel [33] described 2 pa-tients who ingested "a handful" of nuts: one, a 46-year-old female, who experienced hair loss 2 weeks after ingestion; and one, a 38-year-old female, who experienced hair loss 12 days after ingestion. Both patients also reported nausea, dizziness, and grey discoloration of the nails [33].

Colchicine
Colchicine is an alkaloid drug used to treat a number of conditions including familial Mediterranean fever, Behçet's disease, amyloidosis, and gout. It has a narrow therapeutic window, with a reported 100% survival after ingestion of <0.5 mg/kg of colchicine and 100% mortality with ≥0.8 mg/kg via cardiogenic shock and myelosuppression [34][35][36]. Colchicine affects cell division by disrupting mitosis and cell transport systems secondary to arrested microtubule polymerization. Thus, the most affected organs are those with a high rate of cell turnover, such as bone marrow, gastrointestinal tract, and hair [37].
There are 3 stages to the clinical presentation of colchicine toxicity. With the first 24 h after ingestion, common symptoms include nausea, vomiting, diarrhea, and leukocytosis. Multiorgan failure, including bone marrow suppression, occurs in the second stage, 1-7 days after ingestion. Individuals who recover experience the third stage, often characterized by transient alopecia between days 7 and 21 [38][39][40]. However, hair loss may not always be present. In a case series by Alaygut et al. [41], only 1 out of 17 children with colchicine toxicity developed alopecia. The patient was a 16-year-old female who ingested colchicine prescribed for her father's Behçet's disease. Although Bismuth et al. [35,36] reported 100% mortality at 0.8 mg/kg, this patient ingested 0.88 mg/kg of colchicine in a suicide attempt and miraculously survived [41]. In a separately reported suicide attempt, a 17-year-old female ingested 40 mg of colchicine with sudden anagen effluvium of the scalp on the seventh day after ingestion [42]. Case reports of accidental ingestion of prescribed medication also exist, such as in the case of a 3-year-old female who ingested 20 pills (0.7 mg/kg) of colchicine and developed alopecia within 2 weeks [43].
Ingestion may also occur through consumption of natural sources such as plants in the Colchicaceae family, which contain high levels of colchicine. One species, Gloriosa superba, grows in the Sri Lankan wilderness. A retrospective study from western Sri Lanka concluded that G. superba was responsible for 44% of plant poisonings, with a 15% case fatality rate [44]. Premaratna et al. [45] described a case of a 26-year-old male who consumed 2 tubers of G. superba in an attempt to self-harm. The patient began to lose hair on day 9 and became totally alo- pecic by day 14 (Fig. 4) [45]. Senthilkumaran et al. [37] reported a similar case of a 20-year-old male who consumed tubers, instructed by a traditional practitioner, and experienced diffuse loss of scalp hair 6 days later.
Hypervitaminosis A Vitamin A has multiple functions within the body, including skin health, vision, and maintenance of the immune system [46]. Two forms of this vitamin are obtained in the diet: either as a preformed retinol found in dairy products and liver, or provitamin A carotenoids, such as beta-carotene, found in plants. Vitamin A toxicity occurs when ingesting high quantities of the retinol form; betacarotene, even at large doses, is not associated with toxicity [47]. The RDA for the retinol form is 4,000 IU for women and 5,000 IU for men [48]. Vitamin A at toxic levels reportedly causes scalp alopecia as well as loss of eyelashes and eyebrows [12,13,49]. Other symptoms of toxicity include fatigue, malaise, weight loss, nail dystrophy, and flaky skin [48] Individuals taking high-dose supplements or systemic retinoids may be at risk.
Botulinum Toxin Type A Botulinum A injections have been used for years without any known link to alopecia. Recently, however, unilateral madarosis and facial alopecia were reported as a result of long-term use of botulinum A injections for the treatment of orofacial dystonia [50]. In addition, subjective nonscarring frontal alopecia has also been described by Di Pietro and Piraccini [51] in a case series of 5 female patients who had all undergone periodic botulinum A injections for forehead wrinkles. There was no objective measurement of hair loss before the start of injections or after hair loss occurred.
Podostroma cornu-damae Podostroma cornu-damae is a rare and highly toxic species of fungus in the Hypocreaceae family that grows in Eastern Asia and Java. Although the mechanism by which the toxin acts is unknown, several fatalities associated with this fungus have been reported in Japan. Kim et al. [52] described 2 cases in Korea of accidental P. cornudamae poisoning because the patients mistakenly made tea from the toxic fungus, thinking it was Ganoderma lucidum, a popular health food. Only 1 of the patients experienced alopecia 5 days after initial ingestion, as well as fever, weakness, abdominal discomfort, desquamation of hands and feet, and neutropenia [52]. Ahn et al. [53] reported similar cases, also in Korea, of 2 patients poisoned after mistaking P. cornu-damae for G. lucidum. One pa- tient developed hair loss, along with accompanying fever, weakness, chills, and desquamation of palms and soles [53].

MT-45
There has been a rise in synthetic opioids and new psychoactive substances (NPS) on the recreational drug market. MT-45, a synthetic opioid invented in the 1970s, was originally developed as an opioid analgesic, with activity comparable to that of morphine [54,55]. Sold on the internet as "research chemicals," MT-45 and other synthetic opioids have recently been implicated in multiple fatalities.
MT-45 has also been implicated to cause hair loss. Helander et al. [56] described a case series in Sweden of 3 male patients presenting with alopecia following the use of MT-45. Patients experienced hair depigmentation, folliculitis, dermatitis, dry eyes, and elevated liver enzymes, as well as Mees' lines. One patient developed a total alopecia, another patient noted cessation of scalp hair, eyebrow, and eyelash growth, and the last patient experienced uncharacterized hair loss beginning approximately 10 days after MT-45 use [56].

Discussion
Alopecia has a wide differential diagnosis and many causes including nutritional deficiencies, autoimmune disorders, pattern baldness, and exposure to toxic agents. Acute onset of alopecia associated with a number of generalized symptoms may lead the clinician to consider toxic exposure as a cause of alopecia. Multiple agents are known to cause alopecia when found at toxic levels in the human body including heavy metals, selenium, boric acid, vitamin A, prescription drugs such as colchicine, botulinum toxin, synthetic opioids, and fungi.
When assessing for heavy metal toxicity, clinicians should ask about possible occupational exposure, dental work, and diet, especially when hair loss is of acute onset and accompanied by general symptoms such as nausea, vomiting, fatigue, depression, insomnia, irritability, recurrent infections, and neurological symptoms, such as memory loss and tremors. Assessment of household toxic exposures is especially important in children. Clinicians should determine which products are present in the household and if they are safely stored. If an adult presents after the ingestion of household items, especially in the instance of boric acid poisoning, it is important to rule out suicidal ideation and/or attempt. In cases of over-the-counter or prescription drug ingestion, again clinicians should thoroughly assess patients' psychological state to determine if the ingestion was intentional. If a clinician suspects selenosis as a cause for alopecia, ask about supplements or paradise nut intake, as well as accompanying symptoms such as fatigue, nausea, diarrhea, joint pain, and/or nail changes. Clinicians should elucidate if colchicine is available at home (i.e., family members taking colchicine for a medical indication such as gout or Bechet's disease) or if the patient ingested a plant from the Colchicaceae family. In all patients presenting with facial and frontal alopecia, without hair loss in other areas, clinicians should elicit a history regarding regular botulinum toxin use.
Thallium toxicity may occur through a variety of methods including ingestion, inhalation, or mucosal absorption and is defined as a urine thallium level >5 μg/L within 24 h [17]. Thallium exposure can occur through occupational exposure, household use of rodent poisons, and intentional poisoning with malicious intent or secondary to attempted suicide. The triad of thallium poisoning is gastroenteritis, polyneuropathy, and a variety of dermatological symptoms including anagen effluvium within 2-3 weeks of exposure [57]. Although mercury toxicity has become less common, historically it was used for syphilis treatment, with vapor exposure still posing a concern for those working in the manufacturing industry as well as for patients with old-style dental amalgam fillings; another route of exposure is ingestion, found in high levels in the tissue of large deep-sea fish [18,19].
Historically, arsenic was used to treat psoriasis, syphilis, and promyelocytic leukemia; currently, arsenic can be found in high concentration in some seaweed causing toxicity in those individuals who ingest large amounts in their diet [23]. In addition, chronic arsenicosis is a major health concern in areas of the world, such as Bangladesh and neighboring areas, because of ground-water contamination [58]. Affected individuals often present with skin manifestations on their palmar and plantar surfaces; however, a few patients may present with alopecia.
Household items such as insecticides, mouth wash, eye wash, wound irrigation, detergents, and personal care products may contain boric acid [59,60]. Although not easily toxic to an adult, often accidental ingestion of these products by infants or young children may result in poisoning and possibly even fatality. Currently, the mechanism of boric acid toxicity is not well understood and treatment consists of supportive care.
With an increase in the public's awareness of healthy dietary additions, selenium-containing supplements DOI: 10.1159/000485749 have found a larger market. Given that the RDA of selenium is 55 μg, and the average daily intake in the US is reported at >80 μg (tolerated upper limit approx. 400 μg/ day), currently there are no guidelines or recommendations for selenium supplementation in the diet [28,30]. Although it is an essential element for proper cellular function, in large amounts selenium may become toxic. At physiological levels, selenium acts as an antioxidant; however, it may become a pro-oxidant at higher concentrations causing free-radical damage to cellular structures [61].
Colchicine toxicity is often a result of prescription drug overdose, either by accidental poisoning or suicide attempt. Although the reported half-life of colchicine is 9-16 h, it may be longer at higher doses [38,62]. Hair loss often begins 7-14 days after colchicine exposure, accompanied by gastrointestinal symptoms and leukocytosis [42].
Botulinum toxin is a neurotoxic protein produced by Clostridium botulinum. By preventing the release of the neurotransmitter acetylcholine (ACh) at the neuromuscular junction (NMJ), the toxin produces a flaccid paralysis that has been exploited for medical purposes, such as anti-aging, and treating hyperhidrosis, muscle spasticity, and migraines [50,63]. Several reports have described frontal alopecia after the use of botulinum toxin; however, the mechanism remains unknown.
As opposed to the loss of telogen hairs as part of the normal hair cycle, toxicity secondary to some of the substances discussed may result in loss of anagen hairs [10]. Microscopic examination of anagen hairs should reveal tapered, pigmented hair bulbs, with attached root sheathes, as compared to telogen hairs which demonstrate a club-shaped bulb with no pigment or root sheath [64]. Multiple cases involving thallium, colchicine, and selenium toxicity report anagen hairs with or without dystrophic follicles on trichoscopy, light microscopy, and scanning microscopy [5,6,31,37,42,[64][65][66]. Unfortunately, many reported cases did not initially present to dermatology and microscopic examination of the hair was not completed. In cases of hair loss where the inciting factor or diagnosis is unclear, a consultation to dermatology must be included in the workup.

Conclusions
Thallium, mercury, selenium, and colchicine have compelling evidence linking toxic levels of these substances to hair loss. Compounds such as boric acid, vitamin A, botulinum toxin, chemicals found in the fungal species P. cornu-damae, and synthetic opioids, such as MT-45, have less evidence and their role in toxic hair loss is still emerging. Further research will need to be completed to elucidate a pattern and mechanism of hair loss for the aforementioned agents. A familiarity with the typical presentations of alopecia as well as accompanying symptoms can aid to recognize a possible toxic cause of the patient's alopecia.