Health Hazards of Xylene: A Literature Review Keywords: Methyl hippuric acid, Biological exposure index, Occupational safety, Laboratory technicians and xylene toxicity

Xylene, an aromatic hydrocarbon is widely used in industry and medical laboratory as a solvent. It is a flammable liquid that requires utmost care during its usage. On exposure the vapours are rapidly absorbed through the lungs and the slowly through the skin. Prolonged exposure to xylene leads to significant amount of solvent accumulation in the adipose and muscle tissue. This article reviews the various acute and chronic health effects of xylene through various routes of exposure. Sharada T. Rajan and N. Malathi, Health Hazards of Xylene www.jcdr.net Journal of Clinical and Diagnostic Research. 2014 Feb, Vol-8(2):271-274 272 person who had committed suicide by the consumption of xylene. He also observed no other adverse effects to the cardiovascular or gastrointestinal systems. He concluded that the death of the person was due to a centrally mediated depression of the respiratory system [14]. Condie et al., in his animal study of oral exposure to mixed xylene had observed an increase in hyaline droplet change in the male rats and early chronic nephropathic changes in the female rats exposed to mixed xylene for 90 days. It was therefore concluded that such continuous change could result in renal cell damage [15]. In the report of an accidental ingestion of xylene in a person by Recchia et al., it was found that it resulted in a persistent coma for more than 26 hours [16]. Condie et al., in his animal study reported signs of convulsions, hyperactivity, epistaxis and hypersalivation along with increased aggressiveness in rats given mixed xylene for 90 days [15]. deRmAl exposuRe In acute dermal exposure of xylene by hand immersion technique in humans by Engstrom et al., and Riihimaki and Pfaffli, it was reported that it was associated with vasodilatation of the skin of the hand, dryness and scaling of the area and skin erythema of the hand. It was also found that in patients with a history of atopic dermatitis who were symptom-free, it resulted in the development of toxic eczema of the hands of such subjects on exposure to xylene. It was also found that in such patients a three time greater absorption rate of xylene was observed compared to the other subjects in the study [17,18]. Palmer and Rycroft in 1993 also reported the occurrence of urticaria in a female technician of cytology laboratory who was predominantly exposed to vapours of xylene in the occupational environment. It was effectively proved that it was as a result of direct exposure to xylene by the performance of a closed patch test which elicited severe erythema and whealing of the skin [19]. oculAR exposuRe Several studies such as Nelson et al., Uchida et al., and Hake et al., have observed irritation of the eye on exposure to xylene vapours [9,11,20]. Hine and Zuidema in their animal study of instillation of 0.1 ml of mixed xylene directly to the eyes of rabbits resulted in moderate irritation of the eyes [21]. The various literatures on the health effects of xylene are tabulated according to the different routes of exposure [Table/Fig-1-3]. dIscussIon Xylene, a synthetic hydrocarbon produced from coal tar is a widely used as a universal solvent. Various health effects due to xylene exposure have been documented in the literature. A number of theories exist for the mechanisms by which xylene exerts its toxic effects on the various systems of the body. The pulmonary, gastric and ocular effects of xylene are attributed to the irritant nature of the chemical [1]. Some authors have suggested that certain metabolic intermediates such as methylbenzaldehyde may be responsible for the toxic effects of xylene. Inhibition of pulmonary microsomal enzymes by the binding of such toxic metabolites thereby inactivating the enzymes also might contribute to the toxic nature of xylene [22]. The mechanism of nephrotoxicity of xylene may be related to the reactive metabolite formation which subsequently causes irritation of the renal tissues or direct membrane fluidization [1,22,23]. According to Franchini et al., the urinary β-glucuronidase levels in humans exposed to xylene are high thereby indicating a faster turnover of the renal cells due to toxicity of the toxic metabolites of the chemical [24]. Padilla and Lyerly in their study have demonstrated a decrease in the axonal transport of stimuli following xylene exposure [25]. A decreased hypothalamic catecholamine levels following exposure to xylene has been observed by Andersson et al., [26]. The toxic System Type dose Time Signs reference RS unspecified suicide Pulmonary congestion & edema Abu Al Ragheb et al., 1986 [14] Neuro mixed Accidental ingestion Coma for 26 hrs Recchia et al., 1985 [16] [table/Fig-2]: Oral route System Type dose Time Signs & symptoms reference Respiratory system Mixed 200 ppm 3-5 min Nose & throat irritation Nelson et al., 1943 [9] Respiratory system Mixed 10,000 ppm Acute exposure (autopsy) Death, severe lung congestion with focal interalveolar hemorrhage, pulmonary edema Morley et al.,1970 [10] Respiratory system Mixed Unspecified Chronic occupational exposure Labored breathing, impaired pulmonary function Hipolito 1980 [12] Respiratory system p-xylene 100 ppm 1-7.5 hrs/ day for 5 days Nose & throat irritation Hake et al.,1981 [20] Respiratory system mixed 14 ppm 7 yrs Nose & throat irritation Uchida et al.,1993 [11] GI mixed Unspecified Nausea, vomiting, gastric discomfort Hipolito 1980 [12] GI mixed 2 weeks Anorexia, vomiting Uchida et al.,1993 [11] Hematology mixed 14 ppm 7 yrs No effects Uchida et al.1993 [11] Muscle mixed 14 ppm 7 yrs Decreased grasping power & muscle power in extremities Uchida et al.,1993 [11] Hepatic mixed 14 ppm 7 yrs No change in serum biochemical values Uchida et al.,1993 [11] Renal mixed 10,000 ppm Acute exposure Increased blood urea, distal tube academia, decreased urinary clearance of endogenous creatinine, increased βglucuronidase increased albumin, RBC and WBC excretion Morley et al.,1970 [10] Neuro mixed 14 ppm 7 yrs Increased anxiety, forgetfulness inability to concentrate, dizziness Uchida et al., 1993 [11] Reproductive Along with formalin 14 ppm 7 yrs Spontaneous abortions Taskinen et al.,1989 [13] [table/Fig-1]: Inhalational route symptoms of the central nervous system such as dizziness could be attributed to the liposolubility of xylene in the neuronal membrane according to Savolainen and Pfaffli. He has also suggested that xylene disturbs the activity of the proteins that are essential for normal neuronal function [27]. www.jcdr.net Sharada T. Rajan and N. Malathi, Health Hazards of Xylene Journal of Clinical and Diagnostic Research. 2014 Feb, Vol-8(2):271-274 273 Dermal absorption is also a major route of xylene exposure especially among the laboratory workers. Hino et al., has stated that workers with eczema of the hands had higher urinary methyl hippuric acids (xylene metabolite). He has attributed the removal of ceramide of the corneal layer of the skin epithelium thereby leading to the disruption of epithelial barrier to this exaggerated percutaneous absorption of xylene in such atopic individuals [28]. Gunasekar et al., has performed a histopathological study of the rodent skin epithelium exposed to xylene. Separation at the epithelial-connective tissue interface with infiltration of granulocytes was observed. At a molecular level, increased levels of interleukin and inducible nitric oxide synthase protein was observed serving as indicators of skin irritation [29]. Methods to reduce absorption of xylene following its acute exposure have been highlighted in literature. The first step is to immediately remove the person from the source of exposure. Dermal and ocular exposure can be dealt by decontaminating the area by thoroughly washing with tepid water or normal saline and mild soap. In case of oral exposure emesis with ipecac syrup could be done only when one is certain that there is no likelihood of aspiration thereby leading to aspiration pneumonitis [1,30]. Ellenhorn and Barceloux have suggested the usage of activated charcoal in order to limit the absorption of the chemical in the intestines [1,31]. Sevcik et al., has performed haemodialysis and haemperfusion in order to hasten the removal of xylene from the body [1,32]. Although exposure of personnel cannot be completely avoided it can be kept to a minimal by strict adherence to the occupational and safety health guidelines proposed by Agency for Toxins Substance and Disease Registry (ATSDR). The installation of an approved exhaust in the laboratory and a face mask or a full face organic respirator by the laboratory personnel can help limit the inhalational exposure. Impervious laboratory clothing made of Buna-N-Rubber and Viton gloves should be an integral part of the personnel protective equipment [33]. Staff using xylene should have a thorough knowledge of its handling characteristics. Emergency eye wash or quick drench facility should be made available to the personnel [1]. The biological exposure index of xylene according to ACGIH is 1.5 grams of methyl hippuric acid per gram creatinine in the urine of the exposed workers [4]. As the level of urinary methyl hippuric acid correlates to that of xylene exposure, steps should be taken to detect their levels in the urine of workers periodically. Increase in the levels of the urinary metabolite warrants the necessary steps to reduce their exposure [1,4]. In the field of medical technology histopathology technicians are occupationally exposed to xylene as it forms an integral part of pathological laboratory as a clearing agent of tissue samples. In recent years many researchers have identified xylene substitutes [8]. Ankle and Joshi have suggested the usage of diluted dish washing solution (DWS) to deparaffinise histopathological tissue sections [34]. Metgud et al., have done a study to compare the advantages of xylene free methods over conventional xylene during routine tissue processing. They concluded that such alternatives produced equally good histopathological results [35]. Kunhua et al., have suggested the usage of White oil No. 2 and 14% N-Heptane (SBO) as a novel non-toxic xylene substitute [36]. Premalatha et al., have reported that Mineral oil is a bio friendly substitute of xylene for deparaffinisation of histological sections [37]. Buesa and Peshkov have also highlighted the usage of vegetable oils and limonene based substitutes as clearing agents in the place of xylene [38,39]. The introduction of such substitutes can help in circumventing the toxic effects of xylene [38-40]. conclusIon Workers in certain groups are at a greater risk of exposure to high concentrations of xylene. Literature suggests that xylene exposure causes toxic effects of various systems of the body. Personnel coming in contact with xylene should have an understanding of the various toxic effects of the chemical. Proper handling of the chemical, practice of personnel protective techniques and proper disposal of the used and unused chemical according to the state requirements can help limit the toxic health effects of xylene. ReFeRences [1] Toxicological profile for Xylene, U.S. department of Health and Human Services, Public Health Service, Agency for Toxic Substance and Disease Registry, August 1995. [2] Jacobson GA and McLean S. Biological monitoring of low level occupational xylene exposure and the role of recent exposure. Ann Occup Hyg. 2003; 47 (4): 331-36. [3] Riihimaki V and Savolainen K. Human exposure to m-xylene: Kinetics and acute effects on the central nervous system. Ann Occup Hyg. 1980; 23:411-22. [4] John D. Bancroft and Marilyn Gamble. Theory and Practice of Histological Techniques, fifth edition, Churchill Livingstone, 2006. [5] Mao IF, Chang FK and Chen ML. Delayed and competitively inhibited excretion of urinary hippuric acid in field workers co-exposed to toluene, ethyl benzene and xylene. Arch Env Contam Toxicology. 2007; 53: 678-83. [6] Matsui H, Kasao M and Imamura S. J. Chromatography. 1978; 145: 231-36. [7] Sabatini L, Barbieri A, Indiveri P, Mattioli S and Violante FS. Validation of an HPLC-MS/MS for the simultaneous determination of phenylmercapturic acid, benzylmercapturic acid and omethylbenzyl mercapturic acid in urine as biomarkers of exposure to benzene, toluene and xylenes. J.Chromatography B. 2008; 863: 115-22. [8] Kandyala R, Raghavendra SDC and Rajasekharan ST. J Oral Maxillofac Pathol. 2010; Jan-Jun; 14(1): 1-5. [9] Nelson KW, Ege JF Jr and Ross M. Sensory response to certain industrial solvent vapors. J Ind Hyg Toxicol. 1943; 25:282-85. [10] Morley R, Eccleston DW and Douglas CP. Xylene poisoning: A report on one fatal case and two cases of recovery after prolonged unconsciousness. Br Med J.