Zebrafish as an alternative method for determining the embryo toxicity of plant products a systematic review
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The document systematically reviews 12 articles that evaluated the toxicity of various plant products using zebrafish embryos. The plant products tested included caffeine, cannabinoids, nicotine, curcumin, resveratrol, quercetin, rutin, matrine, sophocarpine, and arecoline. The studies assessed endpoints such as mortality, developmental abnormalities, heart rate, locomotor activity, and growth. Many found similar results to mammalian studies, demonstrating zebrafish embryos can be a valid alternative model for toxicity testing of plant products.
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Zebrafish as an alternative method for determining the embryo toxicity of plant products a systematic review
- 1. REVIEW ARTICLE Zebrafish as an alternative method for determining the embryo toxicity of plant products: a systematic review Maria Alice Pimentel Falcão1 & Lucas Santos de Souza1 & Silvio Santana Dolabella2 & Adriana Gibara Guimarães3 & Cristiani Isabel Banderó Walker1 Received: 21 June 2018 /Accepted: 4 October 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract The toxicological assessment of plant products and pharmaceutical chemicals is a necessary requirement to ensure that all compounds are safe to be exposed to humans. Many countries are trying to reduce the use of animals; thus, alternative techniques, such as ex vivo tests, in vitro assays, and ex uteri embryos, are used. Toxicological assays using zebrafish embryos are an advantageous technique because they are transparent, have rapid embryonic development, and do not require invasive tech- niques. This paper comprehensively reviews how toxicity testing with plant products is conducted in zebrafish embryos. The search terms zebra fish, Danio rerio, zebrafish, zebra danio, Brachydanio rerio, zebrafish, and embryos were used to search for English-language articles in PUBMED, SCOPUS, and WEB OF SCIENCE. Twelve articles on plant product toxicity studies using zebrafish were selected for reading and analysis. After analyzing the articles and comparing with results in mammals, it was possible to prove the similarity among the results and thus corroborate the further development of zebrafish as a valid tool in toxicity tests. Keywords Plant products . Toxicity . Embryo . Zebrafish . Danio rerio Introduction In the last decades, natural products have been a rich source for drug discovery as many new drugs have been derived from either natural products or their derivatives (Newman and Cragg 2016). These compounds, which are obtained from plant, microorgan- ism, and marine organism secondary metabolism, have several therapeutic properties and have been the object of several fields of research in the health sciences (Guo 2017). Furthermore, to ensure the adequate protection of human health, it is essential that the potential of natural products to cause toxic effects be evalu- ated. In this sense, toxicological tests may provide information regarding the potentials risks of exposure associated with the compounds (Holmes et al. 2010). The evaluation of toxicity is a challenge in drug discovery and clinical medicine. Approximately one quarter of drug- related problems occur due to drug toxicity (Guengerich and Macdonald 2007). The use of different animal models in tox- icological tests can reduce the risks to human health and be more financially viable (Atta-ur-Rahman and Choudhary 2014). Therefore, different methodologies in non- mammalian models, such as embryo toxicity tests, have been tested for better toxicity assessments (Brannen et al. 2016). Alternative developmental and reproductive toxicity models are in agreement with the principles of the 3Rs (reduc- tion, refinement, and replacement) in animals for regulatory risk assessment. The 3Rs highlight the importance of alterna- tive approaches and replacing animals with non-animal sys- tems. Since the concept was introduced, a number of organi- zations have been formed to promote humane science and the use of alternatives to animals in research (Tannenbaum and Bennett 2015). Responsible editor: Philippe Garrigues * Cristiani Isabel Banderó Walker bandewalk@hotmail.com 1 Laboratory of Neuropharmacological Studies, Department of Pharmacy, Federal University of Sergipe, Av. Marechal Rondon, s/n – Jardim Rosa Elze, São Cristóvão, SE 49100-000, Brazil 2 Laboratory of Parasitology and Tropical Entomology, Department of Morphology, Federal University of Sergipe, Sâo Cristóvão, SE, Brazil 3 Laboratory of Neuroscience and Pharmacological Assays, Department of Health Education, Federal University of Sergipe, Lagarto, SE, Brazil Environmental Science and Pollution Research https://doi.org/10.1007/s11356-018-3399-7
- 2. Rodents are the conventional animal model for toxicity, behavior, and pharmacological assays. However, zebrafish embryos have emerged as a model in toxicology and pharma- cology based on their advantages for fast reproducible tests and high-throughput behavioral screening (Ašmonaitė et al. 2016; Gianoncelli et al. 2015; Winstock et al. 2000), rapid external development, optical transparency, less space and husbandry care, and easy manipulation (Lawrence 2007). The zebrafish genome shares approximately 70% homology with humans, and 84% of its genes appear to be associated with human disease (Gunnarsson et al. 2008; Howe et al. 2013). Recent studies have used zebrafish early life stage test- ing as a tool between in vitro cell-based models and in vivo mammalian models (Beker van Woudenberg et al. 2013). The aim of this review is to systematically examine articles that have evaluated the toxicity of plant products with biological activities in zebrafish embryos and compare these results with others animal models. Methods We performed an initial literature search in February of 2017 and included articles published over the last 10 years. The articles were obtained using different combinations of the key- words including zebra fish, Danio rerio, zebrafish, zebra da- nio, Brachydanio rerio, zebrafish, and embryos in the PUBMED, SCOPUS, and WEB OF SCIENCE databases. Afterwards, the articles were selected according to the fol- lowing inclusion criteria: articles with keywords in the title, abstract, about plant product extracts or isolated compounds, and tests with zebrafish embryos. We excluded articles related to environmental toxicology in this study. Then, two evalua- tors analyzed the articles based on the titles and abstracts, followed by the full text. Disagreements were resolved by a consensus between the two evaluators. Results and discussion Selection of articles The primary search identified 1902 articles, of which 317 were from PUBMED, 774 from SCOPUS, and 811 from WEB OF SCIENCE. In total, 241 articles were indexed in two or more databases and were considered only once, which left 1661 remaining articles. After analyzing the titles, ab- stracts, and full text, 1649 articles that did not meet the inclu- sion criteria were excluded. Thus, 12 articles were selected. The fluxogram illustrates the progressive study selection and numbers from each stage (Fig. 1, Table 1). Plant products tested on zebrafish embryos Caffeine Caffeine (1,3,7-trimethylxantine, Fig. 2) is an alkaloid found in a variety of plants such as coffee and cocoa beans, tea leaves, guarana berries, and the kola nut (European Food Safety Authority (EFSA) 2015). Caffeine acts as a stimulant of the cardiovascular and central nervous systems, can en- hance fundamental aspects of cognitive performance, and can increase attention and vigilance (Nehlig 2010). This drug can cause adverse effects mainly in pregnant women (Snel and Lorist 2011). The Food and Drug Administration recommends 400 mg/ day of caffeine as a maximum safe level for non-pregnant healthy adults, 200 mg/day for healthy pregnant adults, and 3 mg/kg/day for children (Tunnicliffe et al. 2008). The dose of caffeine for pregnant women is lower due to its high lipid solubility and low molecular weight characteristics, which allow the drug to easily cross the placental barrier. The me- tabolism of caffeine is slower in pregnant women and fetuses compared to other individuals because of reduced CYP1A2 activity, the enzyme that accounts for 95% of caffeine metab- olism (Doepker et al. 2016). Because caffeine can alter behav- iors in humans, it might be expected that caffeine can cause behavior defects in developing embryos (Krieger et al. 2016). To study caffeine-induced toxicity, zebrafish embryos were exposed to 35, 75, and 150 mg/kg of caffeine for 12 or 24 h. The embryos displayed a significant decrease in locomotor activity and somite lengths when compared to the control (Chen et al. 2008). Additionally, zebrafish larvae were ex- posed to doses of caffeine ranging from 1 to 1280 μM because high doses (160, 320, 640, and 1280 μM) demonstrated the ability to inhibit locomotor activities in this species; caffeine did not appear to alter locomotor activities at doses as low as 1 μM (Tran et al. 2017). When caffeine administration was intraperitoneal, zebrafish displayed increased locomotor activ- ity at a 10 mg/kg dose. The discrepant findings can be asso- ciated with the different administration routes, i.e., immersion versus the injection-based administration of caffeine (Maximino et al. 2011, 2014). Therefore, caffeine adminis- tered in adult zebrafish also impairs the behavior by inhibiting the locomotor activity of swimming, which may be associated with the anxiogenic effects of caffeine (Neri et al. 2018). Furthermore, caffeine action was verified in other animal models where it was dosed in pregnant rats (23–138 mg/kg). At birth, the researchers observed a reduction in size with the high dosages, and all groups had decreased body weights (Tomaszewski et al. 2016). So, another study demonstrated that chronic caffeine intake (0.3 g/L) in pregnant rats reduced exploratory locomotion (Souza et al. 2015). Gestational and postnatal caffeine intake may induce tolerance to some excit- atory effects of caffeine (Lorenzo et al. 2010). Environ Sci Pollut Res
- 3. Besides zebrafish, caffeine has also been tested in humans. When caffeine was consumed by pregnant women, doses above 540 mg/day impaired fetus growth in length (Bakker et al. 2010). Moreover, the consumption of more than 100 mg/ day caused low birth weights in fetuses (Sengpiel et al. 2013). Through these studies, we verified that caffeine toxicity can be demonstrated by decreased locomotion in adult rats and can improve locomotion when zebrafish are exposed to it intraperitoneally at low doses for 24 h. Beyond that, caffeine causes a decrease in zebrafish body length and low birth weights in humans. Cannabinoid The leaves and flowers from Cannabis plants contain over 100 related Bphytocannabinoid^ compounds with potential central nervous system actions, heterogeneous psychoactive effects, and neuropharmacological actions. The two major neuroactive phytocannabinoids are Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is responsible for the euphoric and psychotomimetic effects of cannabis, whereas CBD does not have these effects but may have anxiolytic and other medicinal effects (Ahmed et al. 2008; Ligresti et al. 2016). For a long time, the main psychotomimetic component of Cannabis, Δ9 -(THC) (Fig. 3), has been used for recreational and medicinal purposes and in religious rituals (Breivogel et al. 1998). Δ9 -(THC) affects the CNS by interfering with the cannabinoid system and modulates synaptic release in mo- tor control, memory, and other brain functions (Pertwee 2006). Cannabinoids remain the most commonly abused illicit substances by pregnant women worldwide (Calvigioni and Hurd 2015). This usage, combined with the fact that one half of all pregnancies in the world are unintentional or unplanned, means that fetuses are probably exposed to Cannabis early (Finer and Zolna 2014). Zebrafish embryos were tested to investigate the effects of cannabinoid exposure during pregnancy. In acute assays, Δ9 - THC demonstrated a biphasic response, increasing hyperac- tivity at a dose of 0.6 mg/L, followed by a suppression of activity dose-dependently at 1.2, 2.4, and 3.4 mg/L. In a chronic assay, zebrafish larvae demonstrated hyperactivity with doses above 1.2 mg/L (Akhtar et al. 2013). These results are consistent with rodents, which reported a stimulation in locomotor activity by THC at low concentrations and suppres- sion at higher concentrations (Taylor and Fennessy 1977). In rodents, an subcutaneous exposure to 10 mg/kg of Δ9 - THC showed hyperactivity at infancy and adolescence but not at adulthood (Mereu et al. 2003). In humans, an exposure to more than four Cannabis cigarettes per week demonstrated low birth weights and fetal growth (El Marroun et al. 2010). Moreover, the evaluation of the data about the exposure of Δ9 -THC in animal models during pregnancy led us to know that it was very harmful to development and behavior to the mother and the fetus. So, the studies in this review demon- strated that cannabinoids may cause low birth weight, hyper- activity (at low doses) and hypoactivity (at high doses), and low fetal growth. Nicotine Nicotine (Fig. 4) is an alkaloid obtained from Nicotiana tabacum (Solanaceae) that originated in North and South America and was introduced in Europe in the sixteenth cen- tury (Robles and Sabriá 2011). Nicotine is ranked among the Fig. 1 Search and selection of articles for the review Environ Sci Pollut Res
- 6. top five most dangerously abused drugs after alcohol, heroin, cocaine, and methamphetamine (Carhart-Harris and Nutt 2013). Maternal smoking is related with a wide range of effects, including low weight at birth, neuropsychological distur- bances, hyperactivity disorder, and anxiety (Ernst et al. 2001). To better understand how nicotine affects development during pregnancy, nicotine was tested in zebrafish embryos. Acute assay results demonstrated that 240-μM nicotine doses caused a maximum velocity of 36 h.p.f. in embryos and that 120- and 240-μM doses promoted hyperactivity at 48 h.p.f. in embryos. In a chronic low-dose assay in zebrafish embryos, nicotine doses of 0.5 and 1 μM did not exhibit hyperactivity (Mora-Zamorano et al. 2016). These results observed in zebrafish embryos may be ex- plained because acute nicotine exposure causes positive rein- forcing effects, including mild euphoria, diminished appetite, and reduced anxiety while also enhancing aspects of attention and cognition (Adams 2017; Heishman et al. 2010). Chronic nicotine users report rewarding sensations, increased comfort, and reduced negative moods; these states are accompanied by negative tension effects (Cohen and George 2013). Fig. 2 Caffeine chemical structure Fig. 3 Δ9-Tetrahydrocannabinol (THC) chemical structure Table1(continued) CompoundConcentrationExposurestageNumberExposuretimeParametersevaluatedCountryRef. 36,48,and 72h.p.f.(maco zebrafish embryos) Polygonummultiflorum (rootextracts) 0,0.05,0.075,0.10,0.125,0.15, 0.20,and0.25%(w/v) 3–4h.p.f. (embryo) 25/test96hToxicity/teratogenicity Melaninformation Vietnam(Thietal.2016) Abbreviations:ABC,abnormalbodycurvature;AE,abdominaledema;BC,bloodcirculation;BCIR,bodycirculation;C,coagulation;COM,congestion;E,edema;FDS,fulldevelopmentofsomite; FDSEL,fulldevelopmentofsomite,tail,eyes,andlens;FED,fulleyedevelopment;FTE,fulltailextension;HAT,hatching;HB,heartbeat;HE,heartedema;HR,heartrate;M,movement;P,pigmentation; SF,somiteformation;TD,taildetachment Environ Sci Pollut Res
- 7. In addition to assays in zebrafish, a study using mice ex- posed to 0.05 mg/mL of nicotine during pregnancy demon- strated higher movement when compared to the control (Shisler et al. 2017). In conclusion, behavioral abnormalities observed in animal models (zebrafish and mice) and humans reinforce the need to interrupt the use of cigarettes during pregnancy in an attempt to avoid hyperactivity, low weight, and other problems that may arise. Curcumin Curcumin (diferuloylmethane, Fig. 5) is a polyphenol derived from the rhizomes of Curcuma longa (Zingiberaceae). Several studies have demonstrated the efficacy and safety of curcumin supplementation in several human diseases such as osteoar- thritis, metabolic syndrome, solid tumors, chronic obstructive (Panahi et al. 2014), pulmonary disease, anxiety and depres- sion (Esmaily et al. 2015), rheumatoid arthritis (Chandran and Goel 2012), and psoriasis (Carrion-Gutierrez et al. 2015). To analyze the safety of curcumin administration in preg- nancy, curcumin was tested in zebrafish embryos and larvae at doses ranging from 0 to 15 μM. Embryos and larvae displayed significantly decreased survival and hatching rates at 7.5 μM or higher. At 15 μM, none of embryos survived more than 2 days of incubation. LD50 values of curcumin on the embryos and larvae (after 24 h of incubation) were 7.5 μM and 5 μM, respectively (Wu et al. 2007). In the same study, larvae hatched from fertilized eggs treated with 5 μM curcumin; higher doses led to the development of bent or hook-like tails, spinal column curving, pericardial sac edema, retarded yolk sac resorption, and shorter body lengths. In addition to studies in zebrafish, curcumin that was orally tested in mice at doses of 100 μL showed anti-angiogenic activities (Gururaj et al. 2002). Also, curcumin administered at doses ranging from 0 to 741 mg/kg in rats did not alter physical appearance, behavior, or reproductive performance. Additionally, there were no effects on fertility, post- implantation loss, parturition, mean litter size, or mean viable litter size at birth (Ganiger et al. 2007). Despite the beneficial effects of curcumin, more studies will be needed to evaluate its teratogenic effects and toxicity. Matrine and sophocarpine Matrine and sophocarpine (Fig. 6) are alkaloids obtained from Sophora alopecuroides L. (Leguminosae), a traditional Chinese herbal that possesses a variety of pharmacological activities, such as anti-tumor, antioxidant, anti-inflammatory, and antiviral properties (Lu et al. 2014; Zhang et al. 2013). Several studies have demonstrated their potent anti-tumor ac- tivities, including inhibiting cancer cell proliferation, revers- ing multidrug resistance, and preventing or reducing chemo- therapy or radiotherapy toxicity when combined with other chemotherapy drugs (Liu et al. 2014; Sun et al. 2012). Matrine and sophocarpine were tested in zebrafish embryos to estimate their toxicological potential and potential risks (Tropepe and Sive 2003). Exposure to matrine and sophocarpine at high concentrations (250 and 180 mg/L, re- spectively) showed frequent malformations at 72 and 96 h.p.f. At 100 mg/L of matrine and 60 mg/L of sophocarpine, expo- sure led to embryo deformity as early as 48 h.p.f. The appear- ance of tail bending, loss of movement, and lack of hatching at 250 mg/L of matrine and 180 mg/L of sophocarpine at 96 h.p.f. occurred in almost all the embryos. The heart rate, distance moved, swimming activity, and swimming speed of zebrafish larvae exposed to matrine and sophocarpine at 120 h.p.f. decreased in a concentration-dependent manner (Tropepe and Sive 2003). These results suggested that sophocarpine and matrine al- tered the motor nervous system and reduced the distance cov- ered by the larvae; these compounds also acted in a non- developmental capacity on embryos by preventing hatching at high doses. Fig. 4 Nicotine chemical structure Fig. 5 Curcumin chemical structure NN O H H H H NN O H H H H Fig. 6 Matrine (left) and sophocarpine (right) chemical structures Environ Sci Pollut Res
- 8. Millettia pachycarpa Millettia pachycarpa Benth. is a plant cultivated in Japan that belongs to the family Leguminosae. It is well known because it is rich in bioactive flavonoids with antihelmintic, anti- inflammatory (Serafini et al. 2010), anti-tumor (Terzuoli et al. 2011), anti-allergic (Kawai et al. 2007), and anti- microbial properties (Cushnie and Lamb 2011). In relation to toxicity, the aqueous extract of this plant was tested in zebrafish embryos, where the LC50 was demonstrat- ed to be 3 μg/mL. Furthermore, developmental abnormalities, such as pericardial edema, yolk sac edema, spinal curvature, and muscle defects, were observed in a dose-dependent man- ner starting at 3 to 7.5 μg/mL in hatched larvae (Yumnamcha et al. 2015). Extracts from this plant have demonstrated high toxicity that affects embryo development. However, more studies are necessary to evaluate the toxicity of M. pachycarpa. Eclipta prostrate and Spilanthes acmella (Linn.) Murr Eclipta prostrata Linn. and Spilanthes acmella (Linn.) Murr. are herbaceous plants in the Asteraceae family. In Asia, S. acmella has been known as the toothache plant because of its analgesic activity produced by bioactive compounds such as spilanthal and flavonoid (Dubey et al. 2013). E. prostrata has many pharmacological activities, such as immune system regulation (Jayathirtha and Mishra 2004) and inflammation promotion (Sawant et al. 2004), and it also prevents liver damage (Ma-Ma 1978). In an attempt to test their toxicities, zebrafish embryos were exposed to six concentrations of E. prostrata (0.01, 0.1, 1, 10, 20, and 40%) and five concentrations of S. acmella (0.01, 0.1, 1, 10, and 20%). The results showed that the embryos showed delayed pigmentation development and incomplete develop- ment of the tail and eyes from concentrations of 1%. At 40%, no hatching was observed, even after 144 h.p.f. (the accepted time is between 48 and 72 h.p.f.) (Spilanthes et al. 2011). These assays showed that E. prostrata and S. acmella can be toxic to embryos causing teratogenicity and may be lethal at high doses, especially as hatching did not occur. Polygonum multiflorum Polygonum multiflorum (Polygonaceae) is one of the most popular traditional Chinese medicines and is an ingredient in many medicines and prescriptions. In China, P. multiflorum has been widely used to treat various diseases that have been commonly associated with aging. A recent study proved that this plant has antioxidant activities (Lv et al. 2007; Wang et al. 2008). Zebrafish embryos were utilized to evaluate the toxicity of P. multiflorum extract at concentrations ranging from 0 to 175 mg/L. No abnormal development was observed up to 87.5 mg/L. Morphological defects were observed from 105 mg/L (heart and yolk sac edema). At the highest concen- tration (175 mg/L), death occurred (Thi et al. 2016). Based on these results, more studies are necessary to eval- uate the toxicity of P. multiflorum, especially due to its use in anti-aging (Cheung et al. 2014; Lin et al. 2008), as it is prob- ably used by women in their reproductive age. Celastrol Celastrol is a terpenoid purified from the Chinese herb (Fig. 7) Tripterygium wilfordii Hook F. (popularly known as thundergod vine), which has been traditionally used as a folk medicine in China (Kuchta et al. 2017). Celastrol has demon- strated various biological properties, including chemopreven- tive, antioxidant, and neuroprotective effects (Jung et al. 2007). Despite having these pharmacological activities, the toxicity of celastrol is poorly understood (Wang et al. 2011). Some tests were conducted in zebrafish embryos to evalu- ate the toxicity of celastrol. The hatching rates of embryos treated with 1.0 μM or higher concentrations of celastrol were significantly lower than that of the negative control. Embryos treated with 0.5 μM or higher concentrations of celastrol also displayed several developmental abnormalities, including no blood flow, pericardial sac edema, and tail malformation. All the embryos died when treated with 2.0 μM of celastrol for 24 h (Wang et al. 2011). Because of the many pharmacological properties of celastrol, additional toxicity assays are necessary to ensure its safety in humans, especially since it has already demon- strated teratogenicity and lethality. Arecoline Arecoline (methyl-1, 2, 5, 6-tetrahydro-1-methyl-nicotinate, Fig. 8) is an alkaloid extract from Areca catechu L. (Arecaceae) that is popularly known as betel quid and is the fourth most used addictive substance in the world after Fig. 7 Celastrol chemical structure Environ Sci Pollut Res
- 9. tobacco, alcohol, and caffeine (Boucher and Mannan 2002; Garg and Chaturvedi 2014; Liu et al. 2016). Arecoline has already been found in the fetal meconium and the placenta, suggesting that mothers may chronically expose their fetuses to arecoline (García-Algar et al. 2005; Pichini et al. 2005). To understand if arecoline can cause ter- atogenicity in zebrafish embryos, embryos were exposed to arecoline treatment (0.001, 0.01, 0.02, and 0.04%). After the exposure, zebrafish displayed smaller lengths when compared to control embryos and exhibited pericardial edema and axial- tail curvature. Arecoline induced general growth retardation in a dose-dependent manner, suggesting that this substance af- fects embryonic development (Peng et al. 2015). In a study with mice, arecoline increased resorption, which led to reduced fetal body weight and decreased mouse embryo viability (Paul et al. 1999). Pregnant women who consumed arecoline had higher incidences of low birth weight and low birth length (Senn et al. 2009). Although the mechanisms of arecoline-induced develop- mental toxicity are unknown, studies have shown that areco- line can affect fetus growth. Thus, more studies are necessary to prohibit or warrant its use during pregnancy. Conclusion The data found in the 12 reviewed articles suggest that toxicity tests can be conducted on zebrafish embryos and the results are comparable to the ones found in rodents and other animal models, indicating the reliability of the zebrafish toxicity stud- ies, once that the findings are similar among the species. Despite the differences about the adaptation to aquatic life, the zebrafish organs are comparable to the humans and dem- onstrate well-conserved physiology. The advantages of the transparent embryos and larvae obtained from zebrafish could provide an invaluable tool for screening the effects of natural product or synthetic drug exposure in a living organism, which may be either toxicological or therapeutic. The trans- parency allows daily visualization and record of development of structures in live embryos. The development of preclinical assays using these models could be used to advance medicine by enabling the identification of novel pharmacological inter- ventions in earlier stages of life. Funding information This study was financed in part by the Conselho Nacional de Desenvolvimento Científico e Tecnológico—Brasil (CNPq), the Fundação de Apoio à Pesquisa e a Inovação Tecnológica do Estado de Sergipe (Fapitec/SE)—Brasil, and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES). References Adams S (2017) Psychopharmacology of tobacco and alcohol comorbid- ity: a review of current evidence. 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