UNITED NATIONS ENVIRONMENT PROGRAMME INTERNATIONAL LABOUR ORGANISATION WORLD HEALTH ORGANIZATION INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 190 XYLENES This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization. First draft prepared by Dr P. Lundberg (National Institute of Working life, Solna, Sweden), Mr P.D. Howe and Dr S. Dobson (Institute of Terrestrial Ecology, Monk's Wood, United Kingdom) and Mr M.J. Crookes (Building Research Establishment, Watford, United Kingdom). Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals. World Health Organization Geneva, 1997 The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO), and the World Health Organization (WHO). The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination of laboratory testing and epidemiological studies, and promotion of research on the mechanisms of the biological action of chemicals. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment. WHO Library Cataloguing in Publication Data Xylenes. (Environmental health criteria ; 190) 1.Xylenes - adverse effects 2.Xylenes - toxicity 3.Environmental exposure I.Series ISBN 92 4 157190 X (NLM Classification: QD 341.H9) ISSN 0250-863X The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available. (c) World Health Organization 1997 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. CONTENTS ENVIRONMENTAL HEALTH CRITERIA FOR XYLENES Preamble 1. SUMMARY 2. IDENTITY, PROPERTIES AND ANALYTICAL METHODS 2.1. Identity 2.2. Physical and chemical properties 2.3. Conversion factors 2.4. Analytical methods 2.4.1. In air 2.4.2. In water 2.4.3. In biological media 188.8.131.52 In blood 184.108.40.206 In urine 220.127.116.11 In exhaled air 18.104.22.168 In human milk 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1. Production processes 3.2. Production levels 3.3. Uses 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION 4.1. Transport and distribution between media 4.1.1. Volatilization 4.1.2. Rain-out 4.1.3. Adsorption 4.2. Transformation 4.2.1. Biodegradation 22.214.171.124 Aerobic degradation 126.96.36.199 Anaerobic degradation 4.2.2. Abiotic degradation 188.8.131.52 Photolysis 184.108.40.206 Atmospheric oxidation 220.127.116.11 Hydrolysis 4.2.3. Bioaccumulation 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1. Environmental levels 5.1.1. Ambient air 5.1.2. Water and sediment 18.104.22.168 Surface water 22.214.171.124 Groundwater 126.96.36.199 Precipitation 188.8.131.52 Leachate 184.108.40.206 Sediment 5.1.3. Soil 5.1.4. Biota 5.2. General population exposure 5.2.1. Source of exposure 220.127.116.11 Air 18.104.22.168 Food 22.214.171.124 Drinking-water 126.96.36.199 Other source of exposure 5.2.2. Xylene levels in human biological samples 5.3. Occupational exposure during manufacture, formulation or use 6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS 6.1. Absorption 6.1.1. In humans 6.1.2. In laboratory animals 6.2. Distribution 6.2.1. In humans 6.2.2. In laboratory animals 6.3. Metabolic transformation 6.3.1. In humans 6.3.2. In laboratory animals 6.4. Elimination and excretion 6.4.1. In humans 6.4.2. In laboratory animals 6.5. Factors affecting toxicokinetics in humans and animals 6.6. Biological monitoring 7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS 7.1. Single exposure 7.1.1. Inhalation studies 188.8.131.52 o-Xylene 184.108.40.206 m-Xylene 220.127.116.11 p-Xylene 18.104.22.168 Technical or undefined xylene 7.1.2. Other exposure routes 7.2. Short-term exposure 7.2.1. Inhalation studies 22.214.171.124 o-Xylene 126.96.36.199 m-Xylene 188.8.131.52 p-Xylene 184.108.40.206 Technical or undefined xylene 7.2.2. Other exposure routes 7.3. Long-term exposure 7.4. Skin and eye irritation; sensitization 7.5. Reproductive and developmental toxicology 7.6. Mutagenicity and related end-points 7.7. Carcinogenicity 7.8. Other effects 8. EFFECTS ON HUMANS 8.1. Acute and accidental exposure 8.2. Controlled human studies 8.3. Occupational exposure 9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD 9.1. Laboratory experiments 9.1.1. Microorganisms 9.1.2. Aquatic organisms 220.127.116.11 Algae 18.104.22.168 Higher plants 22.214.171.124 Protozoa 126.96.36.199 Invertebrates 188.8.131.52 Vertebrates 9.1.3. Terrestrial organisms 10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT 10.1. Evaluation of human health risks 10.1.1. Exposures 10.1.2. Effects 10.1.3. Guidance value 10.2. Evaluation of effects on the environment 10.2.1. Exposure 10.2.2. Effects 10.2.3. Risk evaluation 11. CONCLUSIONS 12. RECOMMENDATIONS 13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES REFERENCES RESUME RESUMEN NOTE TO READERS OF THE CRITERIA MONOGRAPHS Every effort has been made to present information in the criteria monographs as accurately as possible without unduly delaying their publication. In the interest of all users of the Environmental Health Criteria monographs, readers are requested to communicate any errors that may have occurred to the Director of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda. * * * A detailed data profile and a legal file can be obtained from the International Register of Potentially Toxic Chemicals, Case postale 356, 1219 Chātelaine, Geneva, Switzerland (Telephone No. 9799111). * * * This publication was made possible by grant number 5 U01 ES02617-15 from the National Institute of Environmental Health Sciences, National Institutes of Health, USA, and by financial support from the European Commission. Environmental Health Criteria PREAMBLE Objectives In 1973 the WHO Environmental Health Criteria Programme was initiated with the following objectives: (i) to assess information on the relationship between exposure to environmental pollutants and human health, and to provide guidelines for setting exposure limits; (ii) to identify new or potential pollutants; (iii) to identify gaps in knowledge concerning the health effects of pollutants; (iv) to promote the harmonization of toxicological and epidemiological methods in order to have internationally comparable results. The first Environmental Health Criteria (EHC) monograph, on mercury, was published in 1976 and since that time an ever-increasing number of assessments of chemicals and of physical effects have been produced. In addition, many EHC monographs have been devoted to evaluating toxicological methodology, e.g., for genetic, neurotoxic, teratogenic and nephrotoxic effects. Other publications have been concerned with epidemiological guidelines, evaluation of short-term tests for carcinogens, biomarkers, effects on the elderly and so forth. Since its inauguration the EHC Programme has widened its scope, and the importance of environmental effects, in addition to health effects, has been increasingly emphasized in the total evaluation of chemicals. The original impetus for the Programme came from World Health Assembly resolutions and the recommendations of the 1972 UN Conference on the Human Environment. Subsequently the work became an integral part of the International Programme on Chemical Safety (IPCS), a cooperative programme of UNEP, ILO and WHO. In this manner, with the strong support of the new partners, the importance of occupational health and environmental effects was fully recognized. The EHC monographs have become widely established, used and recognized throughout the world. The recommendations of the 1992 UN Conference on Environment and Development and the subsequent establishment of the Intergovernmental Forum on Chemical Safety with the priorities for action in the six programme areas of Chapter 19, Agenda 21, all lend further weight to the need for EHC assessments of the risks of chemicals. Scope The criteria monographs are intended to provide critical reviews on the effect on human health and the environment of chemicals and of combinations of chemicals and physical and biological agents. As such, they include and review studies that are of direct relevance for the evaluation. However, they do not describe every study carried out. Worldwide data are used and are quoted from original studies, not from abstracts or reviews. Both published and unpublished reports are considered and it is incumbent on the authors to assess all the articles cited in the references. Preference is always given to published data. Unpublished data are only used when relevant published data are absent or when they are pivotal to the risk assessment. A detailed policy statement is available that describes the procedures used for unpublished proprietary data so that this information can be used in the evaluation without compromising its confidential nature (WHO (1990) Revised Guidelines for the Preparation of Environmental Health Criteria Monographs. PCS/90.69, Geneva, World Health Organization). In the evaluation of human health risks, sound human data, whenever available, are preferred to animal data. Animal and in vitro studies provide support and are used mainly to supply evidence missing from human studies. It is mandatory that research on human subjects is conducted in full accord with ethical principles, including the provisions of the Helsinki Declaration. The EHC monographs are intended to assist national and international authorities in making risk assessments and subsequent risk management decisions. They represent a thorough evaluation of risks and are not, in any sense, recommendations for regulation or standard setting. These latter are the exclusive purview of national and regional governments. Content The layout of EHC monographs for chemicals is outlined below. * Summary - a review of the salient facts and the risk evaluation of the chemical * Identity - physical and chemical properties, analytical methods * Sources of exposure * Environmental transport, distribution and transformation * Environmental levels and human exposure * Kinetics and metabolism in laboratory animals and humans * Effects on laboratory mammals and in vitro test systems * Effects on humans * Effects on other organisms in the laboratory and field * Evaluation of human health risks and effects on the environment * Conclusions and recommendations for protection of human health and the environment * Further research * Previous evaluations by international bodies, e.g., IARC, JECFA, JMPR Selection of chemicals Since the inception of the EHC Programme, the IPCS has organized meetings of scientists to establish lists of priority chemicals for subsequent evaluation. Such meetings have been held in: Ispra, Italy, 1980; Oxford, United Kingdom, 1984; Berlin, Germany, 1987; and North Carolina, USA, 1995. The selection of chemicals has been based on the following criteria: the existence of scientific evidence that the substance presents a hazard to human health and/or the environment; the possible use, persistence, accumulation or degradation of the substance shows that there may be significant human or environmental exposure; the size and nature of populations at risk (both human and other species) and risks for environment; international concern, i.e. the substance is of major interest to several countries; adequate data on the hazards are available. If an EHC monograph is proposed for a chemical not on the priority list, the IPCS Secretariat consults with the Cooperating Organizations and all the Participating Institutions before embarking on the preparation of the monograph. Procedures The order of procedures that result in the publication of an EHC monograph is shown in the flow chart. A designated staff member of IPCS, responsible for the scientific quality of the document, serves as Responsible Officer (RO). The IPCS Editor is responsible for layout and language. The first draft, prepared by consultants or, more usually, staff from an IPCS Participating Institution, is based initially on data provided from the International Register of Potentially Toxic Chemicals, and reference data bases such as Medline and Toxline. The draft document, when received by the RO, may require an initial review by a small panel of experts to determine its scientific quality and objectivity. Once the RO finds the document acceptable as a first draft, it is distributed, in its unedited form, to well over 150 EHC contact points throughout the world who are asked to comment on its completeness and accuracy and, where necessary, provide additional material. The contact points, usually designated by governments, may be Participating Institutions, IPCS Focal Points, or individual scientists known for their particular expertise. Generally some four months are allowed before the comments are considered by the RO and author(s). A second draft incorporating comments received and approved by the Director, IPCS, is then distributed to Task Group members, who carry out the peer review, at least six weeks before their meeting. The Task Group members serve as individual scientists, not as representatives of any organization, government or industry. Their function is to evaluate the accuracy, significance and relevance of the information in the document and to assess the health and environmental risks from exposure to the chemical. A summary and recommendations for further research and improved safety aspects are also required. The composition of the Task Group is dictated by the range of expertise required for the subject of the meeting and by the need for a balanced geographical distribution. The three cooperating organizations of the IPCS recognize the important role played by nongovernmental organizations. Representatives from relevant national and international associations may be invited to join the Task Group as observers. While observers may provide a valuable contribution to the process, they can only speak at the invitation of the Chairperson. Observers do not participate in the final evaluation of the chemical; this is the sole responsibility of the Task Group members. When the Task Group considers it to be appropriate, it may meet in camera. All individuals who as authors, consultants or advisers participate in the preparation of the EHC monograph must, in addition to serving in their personal capacity as scientists, inform the RO if at any time a conflict of interest, whether actual or potential, could be perceived in their work. They are required to sign a conflict of interest statement. Such a procedure ensures the transparency and probity of the process. When the Task Group has completed its review and the RO is satisfied as to the scientific correctness and completeness of the document, it then goes for language editing, reference checking, and preparation of camera-ready copy. After approval by the Director, IPCS, the monograph is submitted to the WHO Office of Publications for printing. At this time a copy of the final draft is sent to the Chairperson and Rapporteur of the Task Group to check for any errors. It is accepted that the following criteria should initiate the updating of an EHC monograph: new data are available that would substantially change the evaluation; there is public concern for health or environmental effects of the agent because of greater exposure; an appreciable time period has elapsed since the last evaluation. All Participating Institutions are informed, through the EHC progress report, of the authors and institutions proposed for the drafting of the documents. A comprehensive file of all comments received on drafts of each EHC monograph is maintained and is available on request. The Chairpersons of Task Groups are briefed before each meeting on their role and responsibility in ensuring that these rules are followed. WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR XYLENES Members Dr E. Frantik, Centre for Industrial Hygiene and Occupational Diseases, National Institute of Public Health, Prague, Czech Republic Dr U. Hass, Department of Toxicology and Biology, National Institute of Occupational Health, Copenhagen, Denmark Mr P. Howe, Institute of Terrestrial Ecology, Monks Wood Experimental Station, Abbots Ripton, Huntingdon Cambridgeshire, United Kingdom (Co-Rapporteur) Dr Young Lee, Contaminants Standards, Monitoring and Programs Branch, Centre for Food Safety and Applied Nutrition, US Food and Drug Administration, Washington DC, USA Mr G. Long, Health and Welfare Canada, Environmental Health Centre, Tunney's Pasture, Ottawa, Ontario, Canada Dr P. Lundberg, Department of Toxicology, National Institute for Working Life, Solna, Sweden (Co-Rapporteur) Dr Choon-Nam Ong, Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore Dr V. Riihimäki, Institute of Occupational Health, Helsinki, Finland (Chairman) Observer Dr C.J. Bevan, Exxon Biomedical Sciences Inc., East Millstone, New Jersey, USA Secretariat Dr B.H. Chen, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland (Secretary) ENVIRONMENTAL HEALTH CRITERIA FOR XYLENES A WHO Task Group on Environmental Health Criteria for Xylenes met in Geneva from 6 to 9 November 1995. Dr B.H. Chen, IPCS, opened the meeting and welcomed the participants on behalf of the Director, IPCS, and the three IPCS cooperating organizations (UNEP/ILO/WHO). The Task Group reviewed and revised the draft criteria monograph and made an evaluation of the risks for human health and the environment from exposure to xylenes. The first draft of this monograph was prepared by Dr P. Lundberg, Mr P.D. Howe, Mr M.J. Crookes and Dr S. Dobson. The second draft was prepared by Dr P. Lundberg and Mr P.D. Howe incorporating comments received following the circulation of the first draft to the IPCS Contact Points for Environmental Health Criteria monographs. Dr P. Lundberg and Mr P.D. Howe contributed to the final text of the health and environmental sections, respectively. Dr B.H. Chen and Dr P.G. Jenkins, both members of the IPCS Central Unit, were responsible for the overall scientific content and technical editing, respectively. The efforts of all who helped in the preparation and finalization of the document are gratefully acknowledged. ABBREVIATIONS ATPase adenosine triphosphatase BCF bioconcentration factor BTX benzene, toluene, xylene CNS central nervous system DMP dimethylphenol DMSO dimethylsulfoxide EEG electroencephalograph FID flame-ionization detector i.m. intramuscular i.p. intraperitoneal i.v. intravenous LOAEL lowest-observed-adverse-effect level NADPH reduced nicotinamide adenosine dinucleotide NOAEL no-observed-adverse-effect level PB phenobarbital PMBA p-methylbenzyl alcohol POCP photochemical ozone-creation potential RMA reflex modification audiometry s.c. subcutaneous TCE 1,1,1-trichloroethylene 1. SUMMARY Xylene is an aromatic hydrocarbon which exists in three isomeric forms: ortho, meta and para. Technical grade xylene contains a mixture of the three isomers and also some ethylbenzene. The estimated world production in 1984 was 15.4 million tonnes. Xylene is a colourless liquid at room temperature with an aromatic odour. The vapour pressure lies between 0.66 and 0.86 kPa for the three isomers. Approximately 92% of mixed xylenes is blended into petrol. It is also used in a variety of solvent applications, particularly in the paint and printing ink industries. The majority of xylene released into the environment enters the atmosphere directly. In the atmosphere the xylene isomers are readily degraded, primarily by photooxidation. Volatilization to the atmosphere from water is rapid for all three isomers. In soil and water, the meta and para isomers are readily biodegraded under a wide range of aerobic and anaerobic conditions, but the ortho isomer is more persistent. The limited evidence available suggests that bioaccumulation of the xylene isomers by fish and invertebrates is low. Elimination of xylene from aquatic organisms is fairly rapid once exposure has ceased. Typically, mean background levels of all three xylene isomers in ambient air are around 1 µg/m3, but in suburban areas they are around 3 µg/m3. Higher levels have been measured in urban and industrialized areas, mean concentrations ranging up to 500 µg/m3. However, concentrations are generally below 100 µg/m3. Estimated daily exposure of the general population through inhalation is 70 µg in rural areas and less than 2000 µg in urban areas. The concentration in drinking-water ranges from not detectable to 12 µg/litre. The data on the level in food are too limited to estimate daily oral exposure. Mean background concentrations of xylenes in surface water are generally below 0.1 µg/litre. However, much higher values have been measured in industrial areas and areas associated with the oil industry (up to 30 µg/litre in polluted waters and up to 2000 µg/litre near to discharge pipes). Similar background levels have been reported for groundwater although high levels have been reported due to localized pollution from underground storage tanks and pipes. After inhalation exposure the retention in the lungs is about 60% of the inhaled dose. Xylene is efficiently metabolized. More than 90% is biotransformed to methylhippuric acid, which is excreted in urine. Xylene does not accumulate significantly in the human body. Acute exposure to high concentrations of xylene can result in CNS effects and irritation in humans. However, there have been no long-term controlled human studies or epidemiological studies. The chronic toxicity appears to be relatively low in laboratory animals. There is suggestive evidence, however, that chronic CNS effects may occur in animals at moderate concentrations of xylene. Xylene appears not to be a mutagen or a carcinogen. The critical end-point is developmental toxicity, which has been demonstrated at an exposure level of 870 mg/m3 (200 ppm) in rats. Based on this end-point, the recommended guidance value for xylene in air is 0.87 mg/m3 (0.2 ppm). The xylene isomers are of moderate to low toxicity for aquatic organisms. For invertebrates the lowest LC50 value, based on measured concentrations, is for o-xylene at 1 mg/litre (Daphnia magna). The lowest LC50 values recorded for fish are 7.6 mg/litre for o-xylene (rainbow trout; based on measured concentrations), and 7.9 and 1.7 mg/litre for m- and p-xylenes respectively (both for striped bass; based on nominal concentrations). Limited information is available regarding chronic exposure of aquatic organisms to xylenes; however, rapid volatilization makes chronic exposure in water unlikely. The acute toxicity of xylene to birds is low. 2. IDENTITY, PROPERTIES AND ANALYTICAL METHODS 2.1 Identity Xylene exists in three isomeric forms, ortho-, meta- and para-xylene. The commercial product is a mixture of all three isomers with m-xylene predominating, usually 60-70%. The technical product, "mixed xylenes", contains approximately 40% m-xylene and 20% each of ethylbenzene, o-xylene and p-xylene. Small quantities of toluene and C9 aromatic fractions may also be present (Fishbein, 1988). Chemical formula C8H10 C8H10 C8H10 Chemical structure Chemical name ortho-xylene meta-xylene para-xylene Synonyms 1,2-dimethyl- 1,3-dimethyl- 1,4-dimethyl- benzene benzene benzene o-methyltoluene m-methyltoluene p-methyltoluene 1,2-xylene 1,3-xylene 1,4-xylene o-xylol m-xylol p-xylol ortho-xylene meta-xylene para-xylene Relative molecular mass 106.16 106.16 106.16 CAS registry number 95-47-6 108-38-3 106-42-3 RTECS registry number ZE 2450000 ZE 2275000 ZE 2625000 CAS registry number (mixed xylenes) 1330-20-7 RTECS registry number (mixed xylenes) ZE 210000 2.2 Physical and chemical properties Some physical and chemical properties are given in Table 1. Table 1. Some physical and chemical properties of xylenesa o-Xylene m-Xylene p-Xylene Physical state (20°C; 101.3 kPa) liquid liquid liquid Colour colourless colourless colourless Boiling point (°C; 101.3 kPa) 144.4 139.1 138.3 Melting point (°C; 101.3 kPa) -25.2 -47.9 13.3 Relative density (25°/4°C) 0.876 0.860 0.857 Vapour pressure (kPa at 20°C) 0.66 0.79 0.86 Flash point (°C) (closed cup) 30 25 25 Saturation % in air (101.3 kPa) 1.03 (32°C) 1.03 (28°C) 1.03 (27°C) Explosion limits (vol-% in air) 1.0-6 1.1-7 1.1-9 Autoignition temp (°C) 465 525 525 Octanol/water partition coefficient (log P) 3.12 3.2 3.15 Solubility in water (mg/litre) 142 146 185 a Data from Sandmeyer (1981); Verschueren (1983); ECETOC (1986); IARC, (1989); DECOS (1991); Bell (1992) All three isomers of xylene are soluble in organic solvents such as ethanol, diethyl ether, acetone and benzene (ECETOC, 1986; IARC, 1989; DECOS, 1991). At room temperature the xylenes are colourless liquids with an aromatic odour (DECOS, 1991). The odour threshold for mixed xylene in air is approximatively 4.35 mg/m3 (1 ppm) (Carpenter et al., 1975; Amoore & Hautala, 1983; DECOS, 1991). 2.3 Conversion factors 1 ppm = 4.35 mg/m3 at 25°C, 101.3 kPa 1 mg/m3 = 0.23 ppm at 25°C, 101.3 kPa 2.4 Analytical methods 2.4.1 In air US NIOSH has presented a method for measuring aromatic hydrocarbons including xylene, in air. Xylene is adsorbed to coconut shell charcoal, eluated with carbon disulfide and determined using gas chromatography with a flame-ionization detector (FID) (Eller, 1984). A similar method has been described by the International Agency for Research on Cancer (IARC) (Brown, 1988a) concerning airborne vapours of benzene, toluene and xylenes, or mixtures thereof. The concentration range is about 1-1000 mg/m3 (approximately 0.2-200 ppm) in 12-litre air samples. In another method described by IARC (Brown, 1988b) hydrocarbons are adsorbed on a porous polymer, desorbed with heat and transferred with an inert carrier gas into a gas chromatograph equipped with a FID. For a 5-litre air sample the concentration range is approximately 0.5-50 mg/m3 (0.1-10 ppm). With the use of a gas chromatography and mass spectrometry (GC/MS) technique, the detection limit can be as low as 0.2 µg/m3 (Bevan et al., 1991). IARC also presented a method for determinating gasoline hydrocarbons (Brown, 1988c). The air is drawn through two adsorbent tubes in series, containing Chemosorb 106 and charcoal, respectively. The vapour after heat desorption is transferred to a gas chromatograph equipped with a capillary column and FID. The method is suitable for airborne vapours of full-range gasoline over a concentration range of approximately 0.2-100 mg/m3 (0.04-20 ppm) in a 2.5-litre air sample. There are commercially available badges based on passive charcoal sampling. After extraction with carbon disulfide the xylenes can be detected by gas chromatography (Van der Wal & Moerkerken, 1984; Triebig & Schaller, 1986). Xylene can also be detected with infrared analysers with a minimum concentration of 9.6 mg/m3 (2.2 ppm) at a wavelength of 13.1 µm and a pathlength of 20.25 m. This method is only suitable when no other compounds that absorb in the same region are present (DECOS, 1991). Earlier methods for determinating xylenes have been reviewed by Fishbein et al. (1988). 2.4.2 In water A head-space technique coupled to capillary column gas chromatography has been described by Drozd & Novak (1978). The detection limit is at the ppb level. The detection limits could be lowered if the xylenes were extracted from the water by an air stream and condensed in a refrigerated column. In another method, the sample is extracted with hexane or heated in a water bath at 25°C for 1 h. Aliquots are then determined by gas chromatography with FID or mass spectometry. The detection limit is 1 µg/litre (Otson & Williams, 1981; Otson et al., 1982). Recent studies have suggested that with the use of GC/MS the detection limits for xylene in water can be in the range of 0.001 to 0.01 µg/litre (Kenrick et al., 1985; MAFF, 1991). 2.4.3 In biological media A review of biological monitoring of exposure to xylene has been produced; methods include measuring methylhippuric acid in urine, xylene in blood and xylene in expired air (Lauwerys & Buchet, 1988). 184.108.40.206 In blood A method using capillary head-space gas chromatography with FID has been developed for the simultaneous determination of xylene and other aromatic hydrocarbons, such as benzene, xylenes and ethyl- benzene, in blood. The limit of detection is 5 µg/litre and the response is linear between 5 and 4000 µg/litre of blood. A head-space gas chromatographic method for determinating xylenes in blood has also been described (Engström & Riihimäki, 1988a). This method is suitable for the determination of xylene isomers in blood specimens. The detection limit is 53 µg/litre. Ethylbenzene, which normally accompanies xylenes in technical xylene, does not interfere with the determination of xylene. 220.127.116.11 In urine In humans, xylene is metabolized to methylhippuric acids (see section 6.3), which are not normally present in the urine of non-exposed people. The urine methylhippuric acid level has been measured by gas chromatography (Engström & Bjurström, 1978), colorimetry (Ogata & Hobara, 1979), thin-layer chromatography (Bieniek et al., 1982) and high performance liquid chromatography (Ogata & Taguchi, 1986). A suitable gas chromatographic method for the determination of methylhippuric acids in urine has been presented by Engström & Riihimäki (1988b). The range of application is 10-2120 mg/litre. No interference from the normal constituents of urine is seen in the specified range. Another method using HPLC allows methylhippuric acids, phenyl glyoxylic acid and mandelic acid to be determined together with hippuric acid in one run (Angerer, 1988b). The limit of detection is 50 mg/litre of urine and the response is linear up to 2000 mg/litre. The aromatic carboxylic acids excreted in urine do not interfere with the hippuric acid determination. 18.104.22.168 In exhaled air There is a method for determinating benzene, toluene and xylene in breath samples by gas chromatography/mass spectrometry (Pellizzari et al., 1988). The detection limit for xylene is 0.5 µg/m3 and the quantification limit is 2.5 µg/m3. No interference has been observed. The linear range for quantification using fused silica capillaries on a gas chromatograph/mass spectrometer/computer is generally three orders of magnitude. 22.214.171.124 In human milk A purge and trap technique using gas chromatography and electron impact mass spectrometry has been developed by Pellizari et al. (1982) for the detection of xylene and various volatile compounds in human milk. 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1 Production processes Before 1940 virtually all of the aromatic solvents, including xylene, were produced from coal. Thereafter production of xylene from petroleum started. Most mixed xylene is currently produced by catalytic reforming of petroleum. It is also obtained from pyrolysis gasoline as a by-product of olefin manufacture during the cracking of hydrocarbons. Small amounts of mixed xylenes are also obtained from coal-derived coke-oven light oil and from disproportionation of toluene (Fishbein, 1988). There are some differences in the composition of commercial xylenes produced from petroleum and from coal-tar. The general composition of xylenes from petroleum is 44% m-xylene, 20% o-xylene, 20% p-xylene and 15% ethylbenzene. The xylenes from coal-tar consists of 45-70% m-xylene, 23% p-xylene, 10-15% o-xylene and 6-10% ethylbenzene. Commercial xylene may also contain small amounts of toluene, trimethylbenzene (pseu documene), phenol, thiophene, pyridine and non-aromatic hydrocarbons and has frequently been contaminated with benzene (WHO, 1981; Fishbein, 1988). 3.2 Production levels Approximately 3.9 million tonnes of mixed xylenes were isolated in the USA in 1978. The non-isolated mixed xylenes (containing benzene and toluene) are blended into gasoline, while the isolated mixed xylenes are used primarily for the production of the individual isomers and for solvent applications (Fishbein, 1988). World production of p-xylene in 1983 was 3.9 million tonnes of which the USA accounted for 48%, Europe 23% and Japan 16%. The world production of o-xylene in 1983 was 1.3 million tonnes of which western Europe produced 30% and the USA 18%. Eastern Europe was the other large producer of o-xylene (Fishbein, 1988). The approximate world production of o-, p- and mixed xylenes in 1984 was 15.4 million tonnes (ECETOC, 1986). The production of mixed xylenes in 1984 in the USA was 2.78 million tonnes and that of p-xylene was 1.94 million tonnes (Fishbein, 1988). During the same year the production of o-xylene was 316 000 tonnes. The production of mixed xylene and p-xylene in 1994 was 4.1 and 2.8 million tonnes, respectively (Kirschner, 1995). The production of xylenes in some western European countries in 1984 was estimated to be: France 85 000 tonnes, Italy 395 000 tonnes and Federal Republic of Germany 455 000 tonnes. In 1987 the figures were: (in thousands of tonnes) Canada 345, France 129, Federal Republic of Germany 501, India 28, Italy 491, Japan 1767, Republic of Korea 552, Mexico 381 and USA 2772 (IARC, 1989). 3.3 Uses Approximately 92% of the mixed xylenes produced is blended into gasoline. The remainder is used in a variety of solvent applications as well as to produce the individual isomers of xylene. Xylenes are used as solvents, particularly in the paint and printing ink industries. The single largest end-use of mixed xylenes is in the production of the p-xylene isomer. The major derivatives produced from p-xylene are dimethylterephthalate and terephthalic acid used in the production of polyester fibre, film and fabricated items (ECETOC, 1986; Fishbein, 1988). The o-xylene is almost exclusively used to produce phthalic anhydride for phthalate plasticizers, and m-xylene is used for the production of isophthalic acid, an intermediate in the manufacture of polyester resins (ECETOC, 1986; Fishbein, 1988). Mixed xylenes are also used in the manufacture of perfumes, pesticide formulations, pharmaceuticals and adhesives, and in the painting, printing, rubber, plastics and leather industries (IARC, 1989). 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION 4.1 Transport and distribution between media The majority of xylene released into the environment enters the atmosphere directly. This results mainly from its use as a solvent and its release in motor vehicle exhausts. A small proportion is also likely to enter water and soil due to oil/petrol spillages etc. Once in the environment a number of physical processes can affect its distribution. Jori et al. (1986) calculated that more than 99% of the xylene released ultimately partitions to the atmosphere; the calculations were based on the Mackay fugacity model (Mackay et al., 1985). 4.1.1 Volatilization Owing to the relatively high vapour pressure and low water solubility of xylenes, volatilization from water bodies to the atmosphere is likely to be an important distribution process. The half-life for evaporation of o-xylene from water bodies at a depth of 1 metre has been estimated to be around 5.6 h (Mackay & Leinonen, 1975). It is expected that both m-xylene and p-xylene will behave similarly. No information has been reported on the volatilization rate of xylenes from soils, but it is expected to be a fairly rapid process, at least from near to the surface, owing to the reasonably high volatility of xylenes. 4.1.2 Rain-out Xylenes are only slightly soluble in water (see section 2). This means that only a very small proportion of xylene in the atmosphere is likely to be removed by precipitation (rain-out). This is supported by the fact that xylenes have been detected in rainwater samples at only very low levels (2 ng m-xylene/litre and 9 ng p-xylene/litre; see section 126.96.36.199). It is also possible that a small amount of xylene in soil may leach out into aquatic systems. 4.1.3 Adsorption Xylenes are likely to be adsorbed to a small extent onto both aquatic sediments and soil, based on their partition coefficients. However, adsorption is dependent on such factors as the organic carbon content and the water content. Sediment-water partition coefficients of 8.9 for o-xylene and 10.5 for p-xylene have been measured. These were for surface sediment from the Tamar Estuary, United Kingdom, which has an organic carbon content of 4.02% (Vowles & Mantoura, 1987). m-Xylene has been shown to adsorb onto soil to a small extent. Using three soils with organic carbon contents ranging between 0.2 and 3.7%, soil organic carbon-water partition coefficient (Koc) values of 129, 158 and 289 (2.1, 2.2 and 2.5 log values) were measured (Seip et al., 1986). A similar Koc of 219 has been quoted for o-xylene (Pussemier et al., 1990). p-Xylene has been shown to adsorb onto minerals and soils to a small extent from the vapour phase (Rhue et al., 1988). In the absence of water, soils and clay minerals exhibit a large capacity to adsorb p-xylene, owing primarily to adsorption on mineral surfaces. However, such dry conditions are rarely encountered in the environment and may only exist at the soil surface or in arid climates. When the relative humidity is increased to 67% or 90%, the sorption of p-xylene vapour decreases significantly (Pennell et al., 1992). 4.2 Transformation 4.2.1 Biodegradation In soil and water, o- and p-xylene are readily biodegraded under a wide range of aerobic and anaerobic conditions, but o-xylene is much more persistent under similar conditions. 188.8.131.52 Aerobic degradation Bacteria of the genus Pseudomonas have been shown to be capable of growing using either m-xylene or p-xylene as the sole carbon source (Davis et al., 1967; Omori et al., 1967; Omori & Yamada, 1970; Davey & Gibson, 1974). The main initial metabolites appear to be m-toluic acid from m-xylene and p-toluic acid from p-xylene. Similarly, cultures of three strains of Nocardia have been shown to metabolize p-xylene to p-toluic acid and 2,3-dihydroxy- p-toluic acid (Raymond et al., 1969). In contrast to this, many of the bacteria that have been shown to be capable of growing on either m-xylene or p-xylene as sole carbon source do not appear to be capable of growing on o-xylene as sole carbon source (Omori et al., 1967; Davey & Gibson, 1974). o-Xylene has been shown to undergo biodegradation in the presence of other carbon sources. Using hexadecane as growth substrate, o-xylene was co-oxidized to o-toluic acid by Nocardia. A similar oxidation was observed with Pseudomonas using hexane as the growth substrate (Jamison et al., 1976). The biodegradation of xylenes by the autochthonous microflora in groundwater in the presence of the water soluble fraction of gas oil has been demonstrated by Kappeler & Wuhrmann (1978a, 1978b). After a lag period of 3 to 4 days, individual hydrocarbon concentrations were found to decrease at a measurable rate. The removal of m-xylene and p-xylene was complete after 7 days. o-Xylene was shown to degrade at a significantly slower rate than the meta and para isomers, removal being complete after 11-12 days. In each case, the first step in the degradation appears to be oxidation to the corresponding methylbenzyl alcohol. Both m-xylene and p-xylene have been shown to be readily degraded within 13 days using a microbial inoculum from an activated sludge wastewater treatment plant. The initial concentration of xylene was 100 mg/litre and 30 mg/litre of sludge biomass was used. Degradation of xylene was monitored by comparing the oxygen uptake of the system with that of controls (Tabak et al., 1989). The degradation of mixtures of benzene, toluene and p-xylene has been studied using pure cultures of either Pseudomonas sp. strain CFS-215 or Arthrobacter sp. strain HCB, or a mixed culture indigenous to a shallow sandy aquifer. In the mixed culture, the presence of p-xylene was found to increase the lag period before the degradation of benzene and toluene commenced, and also appeared to decrease the rate of toluene degradation compared to the rate obtained without added p-xylene. Degradation of p-xylene occurred in the mixed culture, although a long lag period was observed before degradation commenced. When toluene was also present in the culture, the lag period for the degradation of p-xylene was reduced and the degradation rate was increased, but after all the toluene had been degraded, the p-xylene degradation rate again slowed. In the experiments with Pseudomonas sp., the degradation of p-xylene was slow; no degradation was observed in the first 3 weeks when p-xylene alone was present. Again, the degradation rate of p-xylene was found to increase when toluene was also being degraded. Also, the presence of p-xylene again increased the lag period for benzene and toluene degradation. In the experiments with Arthrobacter sp., degradation of p-xylene was found to occur only in the presence of benzene and at a slow rate (Alvarez & Vogel, 1991). The biodegradation of o-xylene and m-xylene has been studied in three core samples of subsurface soil: uncontaminated soil, soil that had previously been contaminated with unleaded gasoline and soil from an area that had previously undergone biostimulation using hydrogen peroxide. m-Xylene was rapidly degraded in all three core types, although the rate was faster in the previously biostimulated sample due to a higher bacterial cell count ( m-xylene disappeared to below the analytical detection limit within 3 weeks in the previously biostimulated samples, whereas some remained after 3 weeks in the previously contaminated samples). o-Xylene was found to be recalcitrant in all of the samples (Thomas et al., 1990). p-Xylene and o-xylene were shown to be degraded in aquifer material collected from the contaminant plume after a large gasoline spill. The degradation occurred fastest in material from the aerobic degrading zone of the plume, but also occurred rapidly in uncontaminated material (Wilson et al., 1990). In a study using laboratory aquifer columns that simulated saturated-flow conditions typical of a river/groundwater infiltration system, all three xylene isomers were shown to undergo degradation under aerobic conditions. Both m-xylene and p-xylene were degraded to concentrations below the analytical limit of detection within 17 days. The rate of transformation was significantly lower for o-xylene but degradation still occurred readily (Kuhn et al., 1985). The rate of biodegradation of benzene, toluene and xylene (BTX) in groundwater/soil slurries has been shown to be highly dependent on the dissolved oxygen concentration (Chiang et al., 1989). At a dissolved oxygen concentration of between 2 and 8 mg/litre, BTX (initial concentrations between 120 and 16000 µg/litre) was 80-100% degraded in 30-40 days with a half-life of 5-20 days. When the dissolved oxygen concentration was 1 or 2 mg/litre, the BTX was incompletely degraded (20-60%) in 30-40 days. Little or no degradation was observed at dissolved oxygen concentrations of 0, 0.1 and 0.5 mg/litre. The xylenes have been shown to be 100% degraded after 192 h incubation at 13°C with natural flora in groundwater in the presence of other components of high-octane gasoline (Jamison et al., 1976). 184.108.40.206 Anaerobic degradation o-Xylene, along with other alkylbenzene compounds, has been shown to undergo degradation under anaerobic methanogenic conditions. No significant degradation of o-xylene occurred over the first 20 weeks, but after 40 weeks the concentration was reduced to 22% of the original. Less than 1% remained after 120 weeks (Wilson et al., 1986). In anoxic suspensions of Pseudomonas sp. strain T cells grown anaerobically with toluene, m-xylene and p-xylene were partially oxidized to 3- and 4-methylbenzoate, respectively. o-Xylene was not oxidized to 2-methylbenzoate. Suspensions of strain T cells grown anaerobically with m-xylene and incubated with m-xylene at 5°C accumulated 3-methylbenzaldehyde (3.5 µM after 20 min) and 3-methylbenzoate (5 µM after 20 min). After further incubation at room temperature, the three aromatic compounds were completely oxidized within 3 h (Seyfried et al., 1994). Experiments have been carried out using aquifer material from a site containing areas that were either contaminated or uncontaminated with JP-4 jet fuel. Both mixed xylene and the individual isomers were incubated with the aquifer material at 12°C under a nitrogen atmosphere. Both o-xylene and m-xylene were slowly degraded in the uncontaminated aquifer material when added individually, although m-xylene (at 16 mg/litre) also appeared to inhibit the basal rate of denitrification. Using mixed xylenes, a lag period of 30 days was required before biodegradation commenced in the uncontaminated material. m-Xylene and p-xylene were degraded to below the analytical limit of detection within the next 26 days, but the degradation of o-xylene was found to be much slower. In the contaminated aquifer material, much longer lag periods and decreased rates of biodegradation were observed, o-xylene not being significantly degraded over a 6-month period (Hutchins et al., 1991a). In further laboratory experiments using a mixture of benzene and alkylbenzenes, both o-xylene and m-xylene were found to be degraded under nitrate-reducing and nitrous oxide-reducing conditions, but degradation of o-xylene was found to cease once the other alkylbenzenes had been degraded (Hutchins, 1991). In field experiments in the same aquifer, m-xylene and p-xylene were shown to be degraded under denitrifying conditions when nitrate was injected into the aquifer, but no evidence of biodegradation of o-xylene was found (Hutchins et al., 1991b). The three xylene isomers have been shown to be completely mineralized by aquifer-derived microorganisms under sulfate-reducing conditions. The source of the inoculum was a gasoline-contaminated sediment. All microcosms were initially fed a mixture of benzene, toluene, ethylbenzene, o-xylene and p-xylene (about 5 mg/litre of each component). p-Xylene was found to be > 80% degraded within 72 days and o-xylene was > 80% degraded within 104 days. After this initial adaptation period, o-xylene, m-xylene and p-xylene were rapidly degraded by the system without any lag period ( m-xylene co-elutes with p-xylene and, therefore, m-xylene was not added initially) (Edwards et al., 1992). Edwards & Grbic-Galic (1994) reported that o-xylene is completely mineralized by aquifer-derived microorganisms under anaerobic conditions. However, an adaptation period of 200 to 255 days was required before the onset of degradation. Anaerobic degradation was found to be inhibited by the presence of some natural organic substrates and co-contaminants. p-Xylene and o-xylene have been shown to be degraded in anaerobic aquifer material collected from the contaminant plume after a large gasoline spill (Wilson et al., 1990). All three xylene isomers have been shown to undergo degradation under anaerobic denitrifying conditions. The rate was much lower for o-xylene than for the other isomers. Long lag periods were observed in all cases before degradation commenced (Kuhn et al., 1985). Degradation of o-xylene under anaerobic conditions has been hypothesized to explain the distribution of o-xylene in a landfill leachate plume (Reinhard et al., 1984). m-Xylene has been shown to be rapidly mineralized to carbon dioxide in laboratory aquifer columns operated under continuous flow conditions with nitrite as an electron acceptor. The degradation occurred simultaneously with the reduction of nitrite. In contrast to this, the concentrations of o-xylene and p-xylene were only slightly reduced in the experiment. The author noted, however, that the experiments were carried out over a 6-day period after the addition of the new substrate and therefore may not have allowed a build-up of other microorganisms capable of degrading these substrates (Kuhn et al., 1988). The biodegradation of BTX has been shown to occur under anaerobic, denitrifying conditions using shallow aquifer material that had previously been exposed to BTX. o-Xylene and m-xylene were found to be degraded to 15% and 12%, respectively, of the initial concentration (3 mg/litre) after 62 days with added nitrate (Major et al., 1988). Much less degradation occurred under anaerobic conditions in the absence of added nitrate (73% o-xylene remained after 62 days and 59% m-xylene remained after 62 days). These losses were not considered to be significant when compared with sterile controls. Up to 0.4 mM (42.5 mg/litre) m-xylene was found to be rapidly mineralized in a laboratory aquifer column operated in the absence of molecular oxygen with nitrate as an electron acceptor. Quantitative (80%) oxidation of m-xylene to carbon dioxide occurred with concomitant reduction of nitrate. The column was inoculated with denitrifying river sediment that had been continuously fed m-xylene for several months (Zeyer et al., 1986). 4.2.2 Abiotic degradation The xylene isomers are readily degraded in the atmosphere, photooxidation being the most important degradation process. 220.127.116.11 Photolysis Xylenes do not absorb UV-visible radiation appreciably at wavelengths longer than 290 nm. This means that they are unlikely to be directly photolysed in the troposphere or in solution, as the ozone layer absorbs wavelengths shorter than 290 nm. Experiments using xylenes adsorbed on silica gel have shown that the photomineralization rates for all three isomers are low using radiation with a wavelength longer than 290 nm (Gab et al., 1977). 18.104.22.168 Atmospheric oxidation Atmospheric oxidation of xylenes is rapid and proceeds via free-radical chain processes. The most important oxidant is the hydroxyl radical, but xylenes will also react with other species found in the atmosphere, such as alkoxy radicals, peroxy radicals, ozone and nitrogen oxides. The most likely reaction pathways occurring in the atmosphere are hydroxyl radical addition to the aromatic ring and hydrogen abstraction from the alkyl groups by hydroxyl radicals (Gery et al., 1987), although reaction with nitrate radicals may become important at night (Grosjean, 1990). Estimates for the lifetime of xylenes in the atmosphere have been made from smog chamber experiments and from knowledge of the rate constant for reaction with hydroxyl radicals. Atkinson (1985) reviewed the available hydroxyl radical reaction rate constant data and recommended kOH values at 25°C of 1.47 × 10-11 cm3 × molecule-1 × s-1 for reaction with o-xylene, 2.45 × 10-11 cm3 × molecule-1 × s-1 for reaction with m-xylene and 1.52 × 10-11 cm3 × molecule-1 × s-1 for reaction with p-xylene. Based on hydroxyl radical reaction rate constant data, atmospheric lifetimes of 2.6 h for o-xylene, 1.5 h for m-xylene and 2.4 h for p-xylene have been calculated in south-east England (Brice & Derwent, 1978). Lifetimes in the boundary layer of the atmosphere have been calculated by Singh et al. (1986). Using hydroxyl radical reaction rate constants, lifetimes of 9 sunlight hours for o-xylene, 5 sunlight hours for m-xylene and 10 sunlight hours for p-xylene were estimated. Singh et al. (1983) estimated that around 71.3% loss of o-xylene, 87% loss of m-xylene and 67% loss of p-xylene would occur per day (12 sunlight hours) as a result of reaction with hydroxyl radicals. An important point to consider with this data is that the calculated lifetime depends on several factors, including temperature, and also the actual concentration of hydroxyl radicals. It is known that the concentration of hydroxyl radicals depends greatly on the amount of sunlight available. Thus typical figures are around 2 × 106 molecules/cm3 in summer months, falling by approximately a factor of 2 in the winter months (Singh et al., 1986). At night the concentration of hydroxyl radicals is negligible. Even so, it can be seen that xylenes are removed from the atmosphere quite readily by reaction with hydroxyl radicals. It is possible that xylenes will be removed from aquatic systems by similar types of reactions, as hydroxyl radicals are known to exist in aquatic systems (Mansour et al., 1985). The reaction of xylene isomers with NO3 radicals has been studied. The second-order reaction rate constants measured were: o-xylene, k = 3.74 × 10-16 cm3 × molecule-1 × s-1; m-xylene, k = 2.49 × 10-16 cm3 × molecule-1 × s-1; and p-xylene, k = 4.49 × 10-16 cm3 × molecule-1 × s-1. NO3 radicals have been measured in the lower troposphere during night time hours but photodecomposition occurs during daylight at a wavelength of 600 nm. Typical concentrations of NO3 radicals found during the night are 2.4 × 108 molecules/cm3 in a clean atmosphere and 2 × 109 molecules/cm3 in a moderately polluted atmosphere (Sabljic & Güsten, 1990). Using these concentrations, the following half-lives for the reaction of xylene with NO3 radicals at night have been estimated: o-xylene, 15-89 days; m-xylene, 23-194 days; and p-xylene, 13-107 days. These half-lives are much longer than those for the daylight reaction with hydroxyl radicals, but indicate that removal of xylenes from the atmosphere could still occur at night by this route, especially in polluted atmospheres. The xylenes are sufficiently susceptible to photochemical oxidation in the lower atmosphere that they may contribute to tropospheric ozone formation. Derwent & Jenkin (1990) calculated POCPs (Photochemical Ozone Creation Potentials) for xylenes of 41 ( o-xylene), 78 ( m-xylene) and 63 ( p-xylene). The POCP values reflect the ability of a substance to form low-level ozone as a result of its atmospheric degradation reactions, the POCP values being calculated relative to ethylene (a chemical that is thought to be important in low-level ozone formation and is given a POCP of 100) on a unit mass emission basis. 22.214.171.124 Hydrolysis It is considered unlikely that xylenes will hydrolyse under the conditions found in the natural environment. 4.2.3 Bioaccumulation Octanol-water partition coefficients of 3.12, 3.20 and 3.15 (log values) have been determined for o-xylene, m-xylene and p-xylene, respectively. These values indicate that slight bioaccumulation could take place in the environment. Using these values, bioconcentration factors (BCFs) of 138 (2.14) for o-xylene, 158.5 (2.20) for m-xylene and 144.5 (2.16) for p-xylene (log values are given in parentheses) can be estimated using the formula of Veith et al. (1980). Bioconcentration factors (BCFs) of 21.4 (1.33 log value) for o-xylene and 23.6 (1.37 log value) for combined m-xylene and p-xylene have been measured in the eel (Anguilla japonica). The half-life for elimination of m-xylene and p-xylene from the flesh after exposure had ceased was 2.6 days (Ogata & Miyake, 1979). Bioconcentration factors have been measured for all three isomers in the goldfish. The reported BCFs were 14.1 (1.15) for o-xylene, 14.8 (1.17) for m-xylene and 14.8 (1.17) for p-xylene (log values are in parentheses) (Ogata et al., 1984). After exposure to the water-soluble fraction of Cook Inlet crude oil ( o-xylene concentration 0.14 mg/litre; m-xylene concentration 0.15 mg/litre) for 8 days, concentrations of 0.87 mg/kg o-xylene and 0.90 mg/kg m-xylene were found in the Manila clam (Tapes semidecussata). The concentrations in the clam were found to decrease rapidly during the first 7 days after exposure ceased (Nunes & Benville, 1979). A BCF of 9 for mixed xylenes was measured in both the thorax and abdomen of the adult spot shrimp (Pandelus platyceros) when it was exposed to a water-soluble fraction of Prudhoe Bay crude oil (Sanborn & Malins, 1980). The low BCFs indicate that biomagnification of xylenes through the aquatic food chain is unlikely. 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1 Environmental levels Owing to analytical difficulties it is often not possible to quantify m-xylene and p-xylene individually in environmental samples. As a result, a large proportion of the measured levels of these two isomers refer to the combined total of the two. 5.1.1 Ambient Air Measured levels of o-xylene and the combined m-xylene and p-xylene levels are shown in Table 2. Levels of xylene for indoor air are given in section 5.2. Typically, background levels of all three xylene isomers are around 1 µg/m3. Higher levels have been measured in urban areas, showing that vehicle emissions are a significant source of xylenes. Six studies giving measured levels for m-xylene and p-xylene as individual compounds have been reported. One study gave measured levels in Florida, USA, of < 0.09 to 5.5 µg/m3 for m-xylene and < 0.09 to 2.4 µg/m3 for p-xylene (Lonneman et al., 1978). Another gave levels of 0.019 to 2.66 µg/m3 for m-xylene and 0.018 to 1.19 µg/m3 for p-xylene in the Black Forest, Germany (Jüttner, 1988a), while another reported levels of 92.6 µg/m3 for m-xylene and 39.7 µg/m3 for p-xylene in Zurich, Switzerland (Grob & Grob, 1971). Levels of 11.94-25.74 µg/m3 m-xylene and 5.33-11.14 µg/m3 p-xylene were reported for two cities in Taiwan (Hung & Liao, 1991). Average values of 1.5-6.2 µg/m3 m-xylene and 0.44-2.6 µg/m3 p-xylene were found in the Netherlands, with maximum values of 11-70 µg/m3 m-xylene and 4.9-15.9 µg/m3 p-xylene (Guicherit & Schulting, 1985). Kawata & Fujieda (1993) monitored xylene concentrations in the air of Niigata, Japan, in 1991 and 1992. At an urban location, mean m-xylene and p-xylene concentrations were 4.8 and 2 µg/m3, respectively. The m-xylene and p-xylene concentrations at a rural location were 1.8 and 0.7 µg/m3, respectively. Svanberg et al. (1995) measured xylene levels in the air of 17 Swedish towns during the winters of 1992-1993 and 1993-1994. Mean concentrations ranged from 17 to 47 µg/m3 and from 11 to 41 µg/m3 for m/p-xylene for the two winters, respectively, and from 18 to 53 µg/m3 and 12 to 44 µg/m3 for o-xylene. High levels of total xylene have been measured in air samples from within landfill sites in the United Kingdom (Young & Parker, 1983). Levels of between 36 and 77 mg/m3 were reported in domestic landfills, with higher levels (actual levels not reported) being found in some industrial waste landfills. Table 2. Mean measured levels of o-xylene and m/p-xylenes in ambient air Location o-Xylene m/p-Xylene Reference levels levels (µg/m3) (µg/m3) Sydney, Australia 6.63 17.2 Nelson & Quigley (1982) Sweden near car factory 38 264 Petersson (1982) 1 km from the factory 11.6 85.1 background 0.21 0.58 Stockholm, Sweden busy streets 251 and 91 Jonsson et al. (1985) calm streets 28.3 and 15.9 The Netherlands 0.88 - 3.1 Guicherit & Schulting max (1985) 7.5 - 22.5 Black Forest, Germany 0.024-1.77 Jüttner (1988a) Hamburg, Germany 12 sites 4.5-15.2 Bruckmann et al. (1988) Los Angeles, USA 28.7 Altshuller et al. (1971) USA car painting planta 52 158 Sexton & Westberg (1980) 9 miles from the plant 4.5 14.5 background 0.5 2.5 USA, 10 cities 2.48-8.35 4.11-19.95 Singh et al. (1983) USA, 5 cities ND-5.24b 1.03-14.64 Sheldon et al. (1988) Table 2. (Cont'd) Location o-Xylene m/p-Xylene Reference levels levels (µg/m3) (µg/m3) Raleigh, USA, near to 1.9-7.6 5-19.9 Chan et al. (1991b) roads USA, 6 cities 2.78-25.25 1.9-13.1 Singh et al. (1986) USA urban 5.2 1.2 Brodzinsky & Singh (1983) rural 0.41 0.38 Taiwan 2 cities 7.14 and 15.17 Hung & Liao (1991) Niigata, Japan urban 2 Kawata & Fujida (1993) rural 0.83 Finland industrial 207 568 Kroneld (1989) urban 0.143 0.392 Grenoble, France winter 1.9 22.9 Foster et al. (1991) summer 2.4 28.7 Vienna, Austria streets 24.0 50.8 Lanzerstorfer & Puxbaum (1990) suburbs 6.2 10.4 backgrounds 1.9 3.9 Table 2. (Cont'd) Location o-Xylene m/p-Xylene Reference levels levels (µg/m3) (µg/m3) United Kingdom urban 5.43 12.2 Clark et al. (1984) rural 0.75 2.2 Southampton, United Kingdom urban 12 27 Bevan et al. (1991) busy roads 33 69 common land 5 6 Harwell, United Kingdom 2.4 3.9 Jones (1988) max 15.8 max 34.4 a Based on individual samples b ND not detectable (detection limits not states) 5.1.2 Water and sediment 126.96.36.199 Surface water Levels of the individual xylene isomers measured in surface water are shown in Table 3. Typically, background levels of xylenes in surface waters are low (< 0.1 µg/litre). Much higher levels have been measured in some industrial areas and areas associated with the oil industry. Wiesenburg et al. (1981) measured xylenes in brine from an oil production platform in the Gulf of Mexico. Two samples contained 480 and 1800 µg/litre of m/p-xylene and 500 and 1900 µg/litre of o-xylene. Samples were taken from an underwater vent plume from offshore oil production operations in the same region. Xylene concentrations in the surface water were 0.270 µg/litre for m/p-xylene and 0.06 µg/ litre for o-xylene. Water from the discharge pipe contained 2060 µg/litre of m/p-xylene and 1510 µg/litre of o-xylene. It has been reported that motor boats could be a significant source of xylenes in surface water. Measurements were carried out in an entrance canal to a harbour on Lake Constance both before (early morning) and during boat movement on the lake. Levels recorded before boat movements were o-xylene 18 ng/litre, m-xylene 17 ng/litre and p-xylene 39 ng/litre. Levels recorded during the rest of the day were o-xylene 57-481 ng/litre, m-xylene 76-750 ng/litre and p-xylene 62-416 ng/litre. In general, the levels of xylene increased as the number of boats passing the sampling point increased (Jüttner, 1988b). Xylenes were surveyed in surface water in Japan in 1977, 1985 and 1986. No xylene isomers were detected in 1977 (detection limit = 2 µg/litre). In 1985 one out of 21 samples contained xylene at concentrations of 0.021, 0.042 and 0.037 µg/litre for o-, m- and p-xylene, respectively (detection limit = 0.02 µg/litre). In 1986, the concentrations of o- and m-xylene ranged from 0.04 to 1.2 µg/litre in 12 out of 137 samples and 15 out of 126 samples, for the two isomers respectively. p-Xylene was detected in 4 out of 122 samples at concentrations ranging from 0.06 to 0.48 µg/litre (detection limit = 0.03 µg/litre) (EAJ, 1993). 188.8.131.52 Groundwater Table 3 shows levels of xylene measured in groundwater. Typically, background levels of xylenes in aquifers are low (< 0.1 µg/litre). High levels have been reported in contaminated aquifers. The migration of petroleum products from leaking underground storage tanks and pipelines poses a groundwater contamination problem. Gasoline-contaminated groundwater in Los Angeles, USA, contained xylene at a concentration of 153 µg/litre (Karlson & Frankenburger, 1989). Very high levels of o-xylene (4001 µg/litre) and m/ p-xylene (5385 µg/litre) have been measured in a polluted aquifer in Italy. Water was taken from a well at a depth of 30 m and the pollution was thought to be due to leakage from underground solvent storage tanks (Botta et al., 1984). 184.108.40.206 Precipitation Kawamura & Kaplan (1983) measured xylene in rainwater in Los Angeles, USA, during 1982. An m-xylene concentration of 0.002 µg/litre and a p-xylene concentration of 0.009 µg/litre were reported. Table 3. Levels of xylene in water Location Isomera Level (µg/litre)b References Surface water River Lee, UK T detected at a level Waggot (1981) of > 0.1 River Besós, Spain m/p 24 Gomez-Belinchon et al. (polluted) ortho 8.1 (1991) River Llobregat, Spain m/p 4.7 Gomez-Belinchon et al. (polluted) ortho 0.83 (1991) Seawater Off River Humber, UK T < 0.001-29.0 MAFF (1991) Dredged spoil disposal site T < 0.001-0.330 Sewage sludge disposal site T < 0.001 North Sea, off UK coast T < 0.01-0.250 Hurford et al. (1990) River Tees estuary, UK m/p < 0.05-1.1 Harland et al. (1985) ortho < 0.05-1.1 Coastal site, USA m/p 0.0045-0.066 Gschwend et al. (1982) ortho 0.0018-0.025 Barcelona, Spain m/p 0.015-0.072 Gomez-Belinchon et al. ortho 0.004-0.210 (1991) Gulf of Mexico: T 0.002-0.056 McDonald et al. (1988) river mouth Gulf of Mexico: 0.001 chemical outfall Inner harbour of the T 0.04-0.2 McFall et al. (1985) navigation canal of Lake Pontchartrain, USA Table 3. (Cont'd) Location Isomera Level (µg/litre)b References Wastewater Effluent samples from a T 1.82 Kennicut II et al. (1984) Barceloneta waste treatment facility, Puerto Rico (mainly pharmaceutical in origin) Wastewater treatment para influent = 4.40 Michael et al. (1991) plant, Great Lakes Basin effluent = < 1 Groundwater British aquifers para occasionally Kenrick et al. (1985) (uncontaminated sites detected at thought to represent 0.001-0.02 background levels) ortho detected in 19 out of 32 samples. highest = 0.02 mean = 0.011 Groundwater, near para ND-0.5c Barker et al. (1988) landfill site, Hamilton, ortho 0.03-0.5 Ontario, Canada Edwards aquifer, Texas, T up to 0.08 Buszka et al. (1990) USA Groundwater near m/p NDd-50 Slain & Baker (1990) bituminous layers of ortho NDd-21 shale in rock, near a sanitary landfill site, Ontario, Canada Table 3. (Cont'd) Location Isomera Level (µg/litre)b References Groundwater near an m/p 240-830 Stuermer et al. (1982) underground coal ortho 260-590 gasification site in (background was the USA below the limit of detection of 0.5 µg/litre) Groundwater, New Jersey/ T 59-300 Rao et al. (1985) New York, USA a m/p = combined m-xylene and p-xylene; T = total xylene b ND = not detected c detection limit not stated d detection limit = 2 µg/litre 220.127.116.11 Leachate Barker et al. (1988) measured o- and p-xylene in the leachate from a landfill in Hamilton, Ontario, Canada. Xylene concentrations ranged from 30.8 to 123 µg/litre for the ortho isomer and from 12.5 to 191 µg/litre for the para isomer. Leachate from a landfill in Minnesota, USA, contained m-xylene concentrations ranging from 21 to 150 µg/litre and o/p-xylene concentrations ranging from 12 to 170 µg/litre. Both xylene isomers were presented in all six samples collected (Sabel & Clark, 1984). 18.104.22.168 Sediment Tynan et al. (1991) measured levels of xylene in sediment samples taken in Wales, United Kingdom, of up to 23.4 µg/kg and 21.2 µg/kg for o-xylene and p-xylene, respectively. Harland et al. (1985) reported o-xylene levels of 0.6-3.9 µg/kg and combined m/p-xylene levels of 3.4-250 µg/kg in sediment from the River Tees estuary, England. Xylenes were surveyed in sediment in Japan in 1977, 1985 and 1986. No xylene isomers were detected in 1977 (detection limit = 4 µg/kg). In 1985 one out of 21 samples contained o- or m-xylene at concentrations of 1.1 and 2 µg/kg respectively; no p-xylene was detected (detection limits = 0.6 µg/kg for o-xylene, 1 µg/kg for m-xylene and 2 µg/kg for p-xylene). In 1986 o-, m- and p-xylene concentrations ranged from 0.5 to 7 µg/kg (detected in 24 out of 111 samples), 0.5 to 15 µg/kg (detected in 33 out of 118 samples) and 0.5 to 3.8 µg/kg (detected in 12 out of 105 samples), for the three isomers respectively (detection limit = 0.5 µg/kg) (EAJ, 1993). 5.1.3 Soil Levels of 0.15 g/kg ( o-xylene) and 0.4 g/kg ( m- and p-xylene) have been measured at a depth of 75-250 cm in soil from a gasoline station. The soil was thought to be contaminated as a result of leakage from an underground storage tank (Morgan & Watkinson, 1990). 5.1.4 Biota Xylenes have been measured at levels of 16 µg/kg wet weight in oysters from Lake Pontchartrain, Louisiana, USA (Ferrario et al., 1985). Levels of combined m- and p-xylene have been measured in fish and shellfish from three estuarine sites in the USA (Reinert et al., 1983). The levels found were: silverside (Menidia menidia) 100 and 180 µg/kg, ribbed mussel (Modiolus demissus) 100 µg/kg, and grass shrimp (Palaemonetes pugio) 200 µg/kg. Xylenes were monitored in fish during 1986 in Japan. o-Xylene concentrations ranged from 0.8 to 5 µg/kg in 41 out of 137 samples, m-xylene concentrations ranged from 0.86 to 9.2 µg/kg in 45 out of 124 samples and p-xylene concentrations ranged from 0.8 to 3 µg/kg in 28 out of 127 samples (detection limit = 0.8 µg/kg for all three isomers) (EAJ, 1993). 5.2 General population exposure 5.2.1 Source of Exposure 22.214.171.124 Air Otson et al. (1993) pooled aliquots of individual air sample extracts from 757 randomly selected Canadian residences. The composite sample contained o-, m- and p-xylene concentrations of 8, 7 and 6 µg/m3, respectively. Fellin & Otson (1993) studied the seasonal trends of xylene concentrations in the indoor air of 754 randomly selected Canadian homes. Lowest mean concentrations were found in the summer and the highest in the autumn. Mean concentrations ranged from 3.73 to 9.12 µg/m3 for p-xylene, from 6.81 to 26.03 µg/m3 for m-xylene and from 3.03 to 8.19 µg/m3 for o-xylene. Lioy et al. (1991) monitored indoor and outdoor air at three homes in New Jersey, USA during 1987. Indoor concentrations ranged from 6.0 to 20.5 µg/m3 for o-xylene and from 15.2 to 57.5 µg/m3 for p-xylene. Outdoor concentrations ranged from 1.6 to 12.7 µg/m3 for o-xylene and from 4.6 to 36.9 µg/m3 for p-xylene. Weschler et al. (1990) monitored xylene concentrations in the air of a building with a history of occupant health and comfort complaints. o-Xylene concentrations ranged from 2.1 to 9 µg/m3 and m/p-xylene concentrations ranged from 3.9 to 25 µg/m3. The highest xylene concentrations were associated with the lift shaft. The California Total Exposure Assessment Methodology (TEAM) study conducted in 1984 monitored xylenes in outdoor air, personal air and breath samples for 188 people in Los Angeles County (urban) and Contra Costa County (rural area). The 12-h arithmetic means of the xylene concentrations are summarized in Table 4. A second TEAM study was carried out in 1987 with 51 residents of Los Angeles, California. The 24-h arithmetic means of the xylene concentrations in this study are also summarized in Table 4. Daisey et al. (1994) reported the concentrations of xylenes in the air in 12 office buildings in California. The concentration of o-xylene ranged from 1.3 to 6.1 µg/m3 (0.30 to 1.40 ppb) and that of m/p-xylene from 4.0 to 20.0 µg/m3 (0.93 to 4.60 ppb). Levels measured during winter were higher than summer levels for all types of air. Smoking was determined to be the major determinant for the presence of xylene in breath and personal air; concentrations in the breath of smokers were more than double those of nonsmokers. At petrol stations, exposure to vehicle exhaust and the type of employment contributed significantly to increased concentrations of xylene in breath and personal air (Wallace et al., 1988). Higgins et al. (1983) reported that the gas-phase delivery of p-xylene in ultra-low tar delivery cigarette smoke ranged from < 0.01 to 8 µg/cigarette, while the ranges for m- and o-xylene were < 0.01 to 20 µg/cigarette and < 0.005 to 10 µg/cigarette, respectively. Table 4. Mean xylene concentrations in personal air, outdoor air and breath samples (Wallace et al., 1988, 1991) Location Date Sample type m/p-Xylene o-Xylene (µg/m3) (µg/m3) Los Angelesa February 1984 personal airc 28 13 outdoor air 24 11 breath 3.5 1.0 Los Angelesa June 1984 personal air 24 7.2 outdoor air 9.4 2.7 breath 2.8 0.7 Contra Costaa June 1984 personal air 11 4.4 outdoor air 2.2 0.7 breath 2.5 0.6 Los Angelesb February 1987 personal air 43 16 indoor aird 30 12 outdoor aire 18 6.5 breath (median value) 2.5 0.8 Los Angelesb July 1987 personal air 27 9.2 indoor aird 12 4.3 outdoor aire 7.4 2.8 breath (median value) 0.7 0.25 a 12-h arithmetic means of xylene concentration b 24-h arithmetic means of xylene concentration c Air sample collected at the breathing level of the subjects d samples collected in living room-kitchen area e samples collected in backyards of homes Weisel et al. (1992) analysed air within automobiles whilst idling, driving on a suburban route in New Jersey and commuting into New York City. During a 30-min idling period, mean m/ p-xylene concentrations ranged from 1.3 to 42 µg/m3 and o-xylene concentrations ranged from 0.5 to 18 µg/m3. The highest values were recorded during the summer and the lowest during the winter. The mean m/ p-xylene concentrations for the suburban route were 23 and 16 µg/m3 for low and high ventilation, respectively; for o-xylene mean concentrations were 8.6 and 7.5 µg/m3. Xylene concentrations of 23 µg/m3 for m/p-xylene and 8.8 µg/m3 for o-xylene were recorded whilst commuting into New York City; mean xylene levels of 37 µg/m3 ( m/ p-xylene) and 12 µg/m3 ( o-xylene) were measured whilst travelling through a tunnel. Chan et al. (1991) studied exposure of commuters in Boston, USA, to xylenes and found that the highest exposures were associated with commuting by car ( m/ p-xylene = 20.9 µg/m3; o-xylene = 7.3 µg/m3). The levels of xylenes in samples of air in the vicinity of petrol pumps in five Canadian cities were monitored between June and August 1985 and between January and March 1986. Measured mean concentrations of all the isomers of xylene in the immediate vicinity of self-service pumps were 0.716 mg/m3 in the winter and 0.973 mg/m3 in the summer, and ranged from 0.678 to 3.77 mg/m3 and 0.001 to 6.9 mg/m3, respectively (PACE 1987; 1989). p-Xylene represented more than 70% of the mean concentrations for all isomers. van Wijnen et al. (1995) monitored ambient air for traffic-related pollutants in Amsterdam. Maximum mean time-weighted concentrations were as high as 193 µg/m3 for car drivers, 46 µg/m3 for cyclists and 41 µg/m3 for pedestrians. A mean total xylene level of 65 µg/m3 (15.06 ppb) in ambient air was measured in Turin, Italy, throughout 1991 (Gilli et al., 1994). Within a 10-day sampling period, mean concentrations of 85 and 57 µg/m3 (19.50 and 13.13 ppb) were measured in indoor air for day- and night-time sampling, respectively. The corresponding mean concentrations for outdoor air were 82 and 54 µg/m3 (18.82 and 12.31 ppb) for day- and night-time sampling respectively. The mean personal exposure of the volunteers was 84 µg/m3 (19.30 ppb). Monitoring for xylene has been carried out at filling stations in Rome, Italy (Lagorio et al., 1993). The range of measured concentrations from 703 personal samples among 111 workers was 0.003 to 15.37 mg/m3 (mean: 0.32 mg/m3). Bostrom et al. (1994) calculated the average exposure dose for xylenes (o, m and p) to be 11 µg/m3, based on the relationship between nitrogen oxides (NOx) and xylenes, and a mean exposure for the Swedish population of 23 µg/m3 for nitrogen oxides. The exposure of students commuting to school in Taipei City, Taiwan, in 1992 has been reported by Chan et al. (1993). Students commuting by bus were exposed to 222.8 µg/m3 of o-xylene and 418.1 µg/m3 of m/p-xylene. Students commuting by motorcycle were exposed to 524.5 µg/m3 of o-xylene and 926.9 µg/m3 of m/p-xylene. The air in school classrooms was also monitored; the mean concentration of o-xylene was 26.3 µg/m3 and that of m/p-xylene was 46.4 µg/m3. 126.96.36.199 Food o-Xylene has been detected at levels up to 25 µg/kg (mean level 9 µg/kg) in seven samples of dried beans, at a level of 8 µg/kg in split peas and at a level of 3 µg/kg in lentils from the USA (Lovegren et al., 1979). Xylenes have been identified but not quantified in various other food items including cheese from Italy (Meinhart & Schreier, 1986), dry red beans from the USA (Buttery et al., 1975), winged beans and soybeans from the Philippines (del Rosario et al., 1984) and tomatoes and tomato products from Japan (Chung et al., 1983). All three isomers were detected in the volatile compounds from roasted turkeys fed on a basal diet supplemented with tuna oil (Crawford & Kretsch, 1976). 188.8.131.52 Drinking-water All three xylene isomers were detected in all of 14 samples of United Kingdom drinking-water derived from rivers, lowland reservoirs and groundwater (detection limit not stated) (Fielding et al., 1981). Xylenes have been shown to pass through a drinking-water treatment plant unaltered in concentration (Dowty et al., 1975). Otson et al. (1982) monitored 30 Canadian potable water treatment facilities. Mean total xylene concentrations in both raw and treated water were less than the detection limit in this study (1 µg/litre). Maximum values were less than 1 µg/litre for raw water and 8 µg/litre for treated water. When Williams et al. (1982) sampled 12 Great Lakes (Canada) municipal drinking-water supplies, o- and m-xylenes ( m-isomers) were not detected at five of the sites and in 50% of the 22 samples. Detectable concentrations ranged from 1.1 to 12 µg/litre. The concentration of m- and p-xylene in tap water, Toronto, Canada, was reported to be 0.06 µg/litre (City of Toronto, 1990). The concentrations of xylene in seven samples of bottled water ranged from less than the detection limit to 0.07 µg/litre. 184.108.40.206 Other source of exposure The US EPA (Sack et al., 1992) carried out analyses of 1159 household products. The results of the analyses, according to product category, are presented in Table 5. 5.2.2 Xylene levels in human biological samples Xylenes have been detected in human blood at levels of between 0.5 and 160 µg/litre (mean = 5.2 µg/litre) (Antoine et al., 1986). The level was found to be significantly elevated in 7 out of 250 people sampled. m-Xylene has been determined in human whole blood at levels of 10-20 ng/litre (Cramer et al., 1988). Table 5. Mean xylene concentrations in various products m-Xylene o/p-Xylene Product category Number of Products containing Mean concentration Products containing Mean concentration products tested analyte (%) (% w/w) analyte (%) (% w/w) Automotive 167 26.7 10.6 10.0 31.0 Household cleaners and 111 33.3 1.4 - - polishers Paint-related products 463 60.3 4.2 58.2 2.8 Fabric and leather 91 - - 33.3 0.1 treatments Cleaners from electronic 69 - - - - equipment Oils, greases, lubricants 111 9.3 0.2 11.9 0.2 Adhesive-related products 76 9.1 0.2 9.1 0.2 Miscellaneous: 71 - - - - specialized cleaners, rust remover, correction fluid Ashley et al. (1994) monitored blood samples from more than 600 people in the USA third national health and nutrition examination survey. None of the subjects were occupationally exposed to xylenes. Mean concentrations were 0.37 µg/litre for m/ p-xylene and 0.14 µg/litre for o-xylene. Fustinoni et al. (1995) reported that the mean blood concentration of m/p-xylene in non-smoking traffic wardens in Milan, Italy, was 853 ng/litre before the shift and 683 ng/litre at the end of the shift. The level in non-smokers of the clerical environment from the same area was 809 and 629 ng/litre, respectively. Xylenes were detected, but not quantified, in 8 out of 12 samples of breast milk (Pellizzari et al., 1982). Xylenes have been detected in the axilla odour from humans (Labows et al., 1979). Placental transfer of xylene has been shown to occur (Dowty & Laseter, 1976). 5.3 Occupational exposure during manufacture, formulation or use Occupational exposure to xylenes alone is rare. There is usually simultaneous exposure to other compounds, often organic solvents. In one study, however, 10 female laboratory workers had been exposed to xylene (vapour as well as liquid) for about 4 h daily for up to 16 years. Exposure levels, determined by only one measurement in the breathing zone and by only one in the workroom air, were 139 mg/m3 (32 ppm) and 62 mg/m3 (14 ppm), respectively (Proust et al., 1986). A number of studies have been performed on workers occupationally exposed to solvent mixtures including xylenes (e.g. Seppäläinen et al., 1978; Elofsson et al., 1980; Husman, 1980; Lindström et al., 1982; Valciukas et al., 1985; Maizlish et al., 1987; Van Vliet et al., 1987). In a study on spray varnishers (Angerer & Wulf, 1985) 35 male workers were exposed to 2.2-14.8 mg/m3 (0.5-3.4 ppm) o-xylene, 13.9-50.1 mg/m3 (3.2-11.7 ppm) m-xylene, 3.9-18.7 mg/m3 (0.9-4.3 ppm) p-xylene, 1.4-7.5 ppm ethylbenzene, < 1.5 ppm toluene, <1.2 ppm n-butanol, < 35.5 ppm 1,1,1-trichloroethane and several C9 aromatic compounds. Mean 8-h xylene concentrations of 21.7 and 27.8 mg/m3 (5 and 6.4 ppm) were measured in a lacquer/resin spraying operation in a woodworking facility in the USA (Fairfax, 1995). In a study on workers engaged in dip-coating of metal parts the mean xylene vapour concentration was 16.5 mg/m3 (3.8 ppm). The concentration of the isomers were 3.5 mg/m3 (0.8 ppm) o-xylene, 9.1 mg/m3 (2.1 ppm) m-xylene and 3.9 mg/m3 (0.9 ppm) p-xylene (Kawai et al., 1991a). In a study on workers employed in printing, painting or the manufacture of plastic coated wires, there was an exposure to mixtures of toluene and xylenes. Personal air samples were collected and analysed for toluene and the three isomers of xylene. Maximum exposures to xylenes were > 435 mg/m3 (100 ppm) with a time-weighted average of 17.4 mg/m3 (4 ppm). About half of the xylene was m-xylene (Huang et al. 1994). Concentrations of xylenes ranging from 0.4 to 7.0 mg/m3 (0.1 to 1.6 ppm) were measured during full-shift personal exposure monitoring at an axle painting operation in Newark, Ohio, USA (NIOSH, 1991). Breathing zone samples were collected from workers in the liquid inks and paste inks departments of a small printing ink manufacturing factory. The mean full shift concentration of xylene in the liquid inks department was 314 mg/m3 and in the paste inks department 24 mg/m3. Other solvents in the factory were toluene, ethyl acetate, ethanol, isopropanol and n-hexane (Lewis, 1994). During paint operations in an aeronautical factory xylene concentrations (sum of the three isomers) of 14.3 to 167.0 mg/m3 were measured by personal air monitoring. Other solvents present were methyl ethyl ketone, ethyl acetate, n-butyl alcohol, methyl isobutyl ketone, toluene, n-butyl acetate, ethylbenzene, ethylene glycol and monoethylether acetate (Vincent et al., 1994). Similarly, concentrations of xylene (isomer not specified) among printers have been measured to be between 5.6 and 91.3 mg/m3 (1.3 and 21 ppm). Other solvents were acetone, ethyl acetate, methyl ethyl ketone, white spirit, toluene and trichloroethylene (Nasterlack et al., 1994). Levels of xylene to which workers have been exposed in histological laboratories, measured as 8-h time-weighted average, are from about 10.9 mg/m3 (2.5 ppm) to over 304.5 mg/m3 (70 ppm) (Angerer & Lehnert, 1979; Kilburn et al, 1985; IARC, 1989). In a hospital laboratory, levels of up to 1740 mg/m3 (400 ppm) have been measured (Klaucke et al, 1982). In lithographical processes in Poland the mean value in 1968 was 119 mg/m3 and ten years later 130 mg/m3 (Moszczynski & Lisiewicz, 1985), and in a chemical plant in Hungary the mean concentration in air was 47-56 mg/m3 (Pap & Varga, 1987). In a NIOSH study involving conducted environmental monitoring of xylene in various worksites, the concentrations where workers were exposed to gasoline and exhaustion emissions ranged from < 0.08 to 68.3 mg/m3 (0.02 to 15.7 ppm) (NIOSH, 1993a). The concentration in the air in the cab ranged up to 8.7 mg/m3 (2 ppm) (NIOSH, 1993b). The personal breathing zone samples of an indoor parking garage, a medical taxi cab, an automobile dealership/repair shop and a state highway maintenance garage in New York State ranged from < 0.08 to 1.87 mg/m3 (0.02 to 0.43 ppm) (NIOSH, 1993c). The concentration in personal breathing zone samples from workers in automotive maintenance facilities/dealers, repair shops) in Stamford, Connecticut, USA, ranged from < 0.08 to 1.39 mg/m3 (0.02-0.32 ppm) (NIOSH, 1993d). The highest full-shift exposure at an oil refinery in Colombia was 22.2 mg/m3 (5.1 ppm), and all short-term exposures were below the quantifiable concentration of 1.3 mg/m3 (0.3 ppm) (NIOSH, 1994). Kawai et al. (1991b) monitored the exposure of tank truck drivers to xylenes in Japan. Maximum concentrations were 26.5 to 94.8 mg/m3 (6.1 to 21.8 ppm) during loading and 3.9 to 5.96 mg/m3 (0.90 to 1.37 ppm) during a delivery trip. Fustinoni et al. (1995) measured the exposure of traffic wardens to xylenes in Milan, Italy, in 1994. During a 10-day period, the concentration of o-xylene was 48 µg/m3 and of m/p-xylene was 108 µg/m3. Concurrent monitoring of policemen in clerical environments was also carried out; the concentration of o-xylene in indoor air was 32 µg/m3 and of m/p-xylene was 53 µg/m3. 6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS 6.1 Absorption 6.1.1 In humans In humans, absorption of xylenes has been investigated following inhalation of the vapour or dermal application of the liquid. Pulmonary retention of m-xylene became relatively constant at about 60% after the first 5-10 min of exposure to 430 mg/m3 (100 ppm) (Riihimäki et al., 1979a). The determination was made by measurement of atmospheric and exhaled concentrations. In a previous study (Sedivec & Flek, 1976) a pulmonary retention of 62-64% was reported for each xylene isomer at exposure levels of 196-391 mg/m3 (45-90 ppm) for up to 7 h. A relatively constant retention, average 59%, was reported in individuals exposed to varying m-xylene concentrations in the range of 304-957 mg/m3 (70-220 ppm), both at rest and while undergoing intermittent physical exercise (Riihimäki et al., 1979b). A slight reduction in retention was noted when resting individuals subsequently underwent moderately heavy physical exercise. Increased pulmonary ventilation during exercise was found to be associated with a corresponding increase in total uptake of xylenes (Riihimäki et al., 1979b; Åstrand et al., 1978). In resting individuals exposed to 870 mg/m3 (200 ppm) xylene (8.8% o-xylene, 49.4% m-xylene, 1.4% p-xylene, and 40.4% ethylbenzene) the alveolar air level was about 15% of that in inspired air, while 36% was recorded for individuals undergoing heavy exercise (Åstrand et al., 1978). The ratio of m/p-xylene to ethylbenzene was found to be similar in alveolar air and inspired air. This indicates similar rates of pulmonary absorption for xylenes and ethylbenzene. In this study, o-xylene was not measured (Engström & Bjurström, 1978). During inhalation exposure in resting subjects, a levelling of the blood xylene concentration began after about 15 min of exposure to 435-870 mg/m3 (100-200 ppm) xylene. Light exercise increased the blood level of xylene and indications of plateauing were noted after about 2 h (Åstrand et al., 1978). In another study, an exposure to 435-1261 mg/m3 (100-290 ppm) m-xylene revealed a rapid rise in xylene blood levels during the first hour. Repeated exposure to 430 mg/m3 for 4.5 days (6 h/day) gave rising pre-exposure morning blood levels, indicating some accumulation of m-xylene (Riihimäki et al., 1979a; Riihimäki et al., 1982a,b). Dermal absorption of xylenes has been studied after exposure to the vapour or the liquid. Liquid xylenes (about 0.2 ml of the individual isomers) were applied to the forearm. Uptake into the skin was calculated by measuring the remained material after 5-15 min (Dutkiewicz & Tyras, 1968). Uptake values of 50-160 µg/cm2 per min were reported. However, it should be noted that not all the xylene taken up necessarily penetrated the skin and was absorbed. In more recent studies, dermal absorption has been studied following hand immersion in liquid m-xylene for 15-20 min. Absorption, estimated from the urinary level of the metabolite m-methylhippuric acid, was recorded to be about 2 µg/cm2 per min in eight volunteers (Engström et al., 1977). The amount absorbed (about 35 mg) through both hands was estimated to be equal to the amount absorbed through inhalation of 435 mg/m3 (100 ppm) during the same time. Another group (Lauwerys et al., 1978) obtained a similar value for dermal absorption (2.45 µg/cm2 per min) based on urinary levels of m-methylhippuric acid and m-xylene levels in exhaled breath. Dermal exposure of m-xylene vapour has been investigated in volunteers exposed to 1305 mg/m3 (300 ppm) (two men) or 2610 mg/m3 (600 ppm) (three men) for 3.5 h. Inhalation was excluded by means of a full facepiece supplied-air respirator with overpressure inside the mask. The volunteers were dressed in pyjamas and performed exercise to raise the skin temperature and perspiration (Riihimäki & Pfäffli, 1978). Dermal absorption appeared to be directly dependent on vapour concentration. At 2610 mg/m3 the absorption was calculated to be approximately 0.01 µg/cm2 per min. In a further experiment, three subjects were exposed to 87 mg/m3 (20 ppm) without respirator. In this case both pulmonary and dermal absorption could occur. The total absorption of m-xylene in this experiment was calculated to be of the same order of magnitude as after dermal-only exposure to 2610 mg/m3. 6.1.2 In laboratory animals Absorption of xylene was recorded following whole-body exposure of mice to ring-labelled 14C- m-xylene vapour for 10 min. Based on autoradiograms the absorption was primarily through respiration (Bergman, 1979; Bergman, 1983). All xylenes are well-absorbed orally by rats, based on urinary metabolites. Peak blood levels were reported 4 h after an oral dose of 0.5-4 g m-xylene/kg body weight or 1.1 g p-xylene/kg body weight (Gut & Flek, 1981). The rate of absorption of liquid o-xylene across excised rat skin has been calculated to be 0.103 µg/cm2 per min at steady state (Tsuruta, 1982). 6.2 Distribution 6.2.1 In humans Little information is available on the distribution of xylenes in humans. A peritoneal fat/air partition coefficient of 3605 has been determined for m-xylene in vitro (Sato et al., 1974). The times required to reach equilibrium in tissues have been calculated from physiological parameters. It is estimated to be a few minutes for well-perfused parenchymal organs, a few hours for muscles and several days for adipose tissue (Riihimäki & Savolainen, 1980). Postmortem analysis on a woman who had swallowed xylene 4 days prior to death, revealed xylene to be present in all tissues investigated (Takatori et al., 1982). The ratios of the three isomers (ortho: meta: para) were 3:5:2 in the stomach content, 3:6:1 in blood and 4:4:2 in adipose tissue. In the brain, liver, spleen, kidney and myocardium, however, the o-xylene accounted for about 80%. When volunteers were exposed to 435 to 870 mg/m3 (100 to 200 ppm) mixed xylenes for 2 h, the ratio of m/p-xylene to ethylbenzene was similar in subcutaneous fat and inspired air up to 22 h post-exposure (Engström & Bjurström, 1978). In another study volunteers were exposed to 391-870 mg/m3 (90-200 ppm) m-xylene 6 h per day 5 days per week (plus an additional day after the weekend) (Engström & Riihimäki, 1979). The proportion of absorbed m-xylene distributed to subcutaneous fat was calculated to be about 4% in resting individuals and 8% in those undergoing exercise. Two adult male and two adult female volunteers were exposed by inhalation to < 108-217 mg/m3 (25-50 ppm) of m-xylene (Laparé, 1993). Doubling the exposure concentration led to a proportional increase in the concentrations of unchanged solvents in alveolar air and blood at the end of a 7-h exposure period. Cumulative urinary excretion of the metabolites exhibited a nearly proportional increase. It is also suggested that alveolar air solvent concentration is a reliable index of exposure to m-xylene. 6.2.2 In laboratory animals The distribution of xylene has been studied in male rats exposed to about 217 mg/m3 (50 ppm) 14C-labelled p-xylene for 8 h (Carlsson, 1981). The highest concentrations were present in the kidneys (up to about 1000 nmol/g tissue) and subcutaneous fat (up to more than 250 nmol/g tissue). Higher concentrations than in blood were also found in the ischiatic nerve. Lower concentrations than in blood were found in the cerebrum, cerebellum, muscle and spleen. Elimination half-times from fat were estimated to be 2-7 h. In pregnant rats, o-xylene has been shown to cross the placenta. The concentrations in fetal blood were 25-30% of that in maternal blood after a 2-h exposure (Ungvary et al., 1980). o-Xylene was also detected in amniotic fluid. The concentration of m-xylene in perirenal fat and cerebrum was positively correlated to exposure levels in rats exposed to 217 to 3262 mg/m3 (50 to 750 ppm) m-xylene 6 h/day, 5 days/week for 1-2 weeks (Savolainen & Pfäffli, 1980; Elovaara et al., 1982). Accumulation in perirenal fat has also been shown in rats exposed to 1305 mg/m3 (300 ppm) xylene (80% m-xylene, 12% p-xylene) 6 h/day, 5 days/week for 1-2 weeks (Savolainen et al., 1979a,b). In a similar study with 1305 mg/m3 m-xylene, no accumulation in perirenal fat or brain tissue was recorded after one week (Elovaara et al., 1982). When rats were exposed to 1305 mg/m3 xylene (19.2% o-xylene, 43.0% m-xylene, 19.5% p-xylene, 18.3% ethylbenzene) during 6 h/day, 5 days/week for 18 weeks, a progressive increase of xylene levels in perirenal fat was demonstrated over the first 2 weeks followed by a decline (Elovaara et al., 1980). The decline was attributed to xylene inducing its own metabolism. Similar results were obtained in a study where rats were exposed to 1305 mg/m3 xylene (85% m-xylene, 15% o-xylene) (Savolainen et al., 1979a,b). The tissue distribution of 14C-labelled xylenes has been studied in mice by low-temperature whole body autoradiography (Bergman, 1979; Bergman, 1983; Ghantous & Danielsson, 1986). When male mice were exposed to about 1435 mg/m3 (330 ppm) m-xylene for 10 min, high levels of radioactivity was found immediately post-exposure in body fat, bone-marrow, brain (white matter), spinal cord, spinal nerves, liver and kidney. Radioactivity in the nervous system and fatty tissues was due to xylene alone and was present for 1 and 8 h, respectively. High levels of xylene metabolites were recorded in blood, lung, liver and kidney for up to 8-h post-exposure and in intestinal contents, bronchi and nasal mucosa up to 24 h (Bergman, 1979; Bergman, 1983). Autoradiography of male mice following 10 min inhalation of radioactively labelled p-xylene revealed an accumulation of non-volatile metabolites in the nasal mucosa and the olfactory bulb of the brain. It was assumed that the activity represented aromatic acids (methyl hippuric acid and toluic acid) (Ghantous et al., 1990). The same technique has been used to study distribution of radioactivity after exposure of pregnant mice to about 8700 mg/m3 (2000 ppm) 14C-labelled p-xylene for 10 min (Ghantous & Danielsson, 1986). High concentrations of xylene were recorded in the adult brain and lung with lesser amounts in kidney and liver. At all stages of gestation studied (days 11, 14, 17) p-xylene appeared to pass immediately from dam to embryo/fetus. The concentration in fetus, however, was low; 2% of that in maternal brain. Xylene was evenly distributed in the fetus following exposure on day 11. After exposure on day 17 the xylene was located primarily in the liver (Ghantous & Danielsson, 1986). In a study where rabbits were exposed to xylene (27% o-xylene, 52% m-xylene, 21% p-xylene) for several months, the concentration was reported to be higher than in blood in the adrenals, bone-marrow and spleen (Fabre et al., 1960). Due to the limited nature of the study it is impossible to draw any firm conclusions. Partition coefficients have been determined in vitro for m-xylene using tissue homogenates and blood (Sato et al., 1974). The following blood/air values were reported: 20 (pig blood), 21 (rabbit plasma) and 37 (rabbit blood). Tissue/blood partition coefficients reported were 1.6-2.1 (muscle, kidney, heart and lung), 3.0-3.3 (liver and brain), 42 (bone-marrow) and 146 (peritoneal fat). The relatively low value for brain tissue has been attributed to the content of phospholipids in which xylenes are less soluble than in neutral fat (Riihimäki & Savolainen, 1980). 6.3 Metabolic transformation 6.3.1 In humans Fig. 1 shows schematically the metabolic pathways for xylene ( m-xylene is used as an example) in humans. Metabolism of xylenes by humans consists primarily of side-chain oxidation to form methylbenzoic acid (Sedivec & Flek, 1976; Riihimäki et al., 1979a; Riihimäki et al., 1979b). Methylbenzoic acid is conjugated principally with glycine and excreted in urine as methylhippuric acid. It has been estimated that glycine conjugation would be saturated in humans exposed to about 1174 mg/m3 (270 ppm) xylene while working and to about 3393 mg/m3 (780 ppm) while resting (Riihimäki, 1979a). A small amount of the glucuronide ester of methylbenzoic acid and trace levels of methylbenzyl alcohol have been detected in human urine (Ogata et al., 1980; Engström et al., 1984; Campbell et al., 1988). Hydroxylation of the aromatic ring with the formation of dimethylphenols seems to be a minor pathway in humans. The following dimethylphenol isomers have been identified in human urine: 2,3- and 3,4-dimethylphenol (with o-xylene), 2,4-dimethylphenol (with m-xylene) and 2,5-dimethylphenol (with p-xylene) (Sedivec & Flek, 1976; Engström et al., 1984). 6.3.2 In laboratory animals Most studies on metabolism of xylenes have been performed on rat. The principal pathway involves side-chain oxidation to methylbenzoic acid via methylbenzyl alcohol and methylbenzyl aldehyde. Methylbenzoic acid is then conjugated with glycine or glucuronic acid (Sugihara & Ogata, 1978; Ogata et al., 1980; Elovaara et al., 1984). Conjugation with glycine to form methylhippuric acid predominates for m- and p-xylene (Sugihara, 1979; Ogata & Fujii, 1979; Elovaara et al., 1984). In the case of o-xylene, glucuronide formation has been reported to predominate (Ogata et al., 1980). A separate minor pathway resulting in urinary excretion of thioethers has been studied (Van Doorn et al., 1980; Van Doorn et al., 1981). This pathway appears to be more important for o-xylene than for the other isomers. Hydroxylation of the aromatic ring with the formation of dimethylphenols has been reported to be another minor metabolic pathway in rats (Bakke & Scheline, 1970; Elovaara et al., 1984). Methylbenzoic acid and dimethylphenols are present in urine of guinea-pigs and rabbits exposed to xylene isomers (Fabre et al., 1960). After oral dosing of rabbits with xylenes the main metabolite was methylbenzoic acid (Bray et al., 1949). The acid was considered to be mostly present as the glycine conjugate, methylhippuric acid. Studies with isolated perfused livers and lungs from rabbit indicate differences in the metabolic pathways between these two organs (Smith et al., 1982). In the liver p-methylhippuric acid was the major metabolite detected. In the lung p-methylbenzyl alcohol and p-methylbenzoic acid were the main metabolites detected. There was formation of 2,5-dimethylphenol in the lungs but not in the liver. Metabolism of m- and p-xylenes to m- and p-methylbenzyl alcohols has been found to be greater with hepatic than with pulmonary microsomes (Harper, 1975; Toftgård et al., 1986). Further metabolism to methylbenzoic acid occurred in the presence of hepatic but not pulmonary cytosolic fraction. Daily exposures to xylene increased the activities of liver microsomal enzymes and concentrations of cytochrome P450 (Elovaara et al., 1982; Pathiratne et al., 1986). Metabolism of m-xylene by cerebral microsomal preparations was reported to be very slow (Elovaara et al., 1982). No definitive studies have been reported showing which microsomal P-450 enzymes are involved in xylene metabolism. However when rats were given m-xylene (1.0-1.4 ml/kg body weight) by gastric intubation once daily for 3 consecutive days and killed 24 h after the last treatment, xylene caused an induction of CYP2B and CYP2E1 in liver microsomes (Raunio et al., 1990). Exposure of male Wistar rats to each of the xylene isomers by inhalation at a concentration level of 4000 mg/m3 for 20 h/day over 4 days similarly induced hepatic CYP2B1, while CYP2E1 was reduced, as estimated by Western blots (Gut et al., 1993). 6.4 Elimination and excretion 6.4.1 In humans Absorbed xylenes are excreted mainly as metabolites in urine. Small amounts are excreted unchanged in exhaled air. Excretion in faeces appears to be unimportant. The rate of clearance of p-xylene from blood has been calculated to be 2.6 litres/kg per hour at 87 mg/m3 (20 ppm) and 1.6 litres/kg per hour at 304 mg/m3 (70 ppm) (Wallén et al., 1985). When volunteers were exposed to a constant concentration of about 391-870 mg/m3 (90-200 ppm) m-xylene over 5 days, at least 97% was calculated to be excreted as m-methylbenzoic acid conjugates. 2,4-Dimethylphenol conjugates accounted for 1-2% of the metabolites (Riihimäki et al., 1979a; Riihimäki et al., 1979b). When volunteers were exposed to about 195 mg/m3 (45 ppm) of o-, m- or p-xylene for 8 h, about 95-99% of the dose was excreted as methylhippuric acid in urine. Dimethylphenol excretion was estimated to be 0.1 to 2% of the dose absorbed (Sedivec & Flek, 1976). About 90% of the absorbed dose of m-xylene was excreted as methylhippuric acid after exposure to 435 mg/m3 (100 ppm) for 4 h (Lauwerys et al., 1978; Campbell et al., 1988). On the other hand, after exposure to 600 mg/m3 (138 ppm) of o-xylene, only 46% was excreted in urine as methylhippuric acid and only trace amounts of the o-methylbenzoyl glucuronide were detected (Ogata et al., 1980). In a study of 121 male workers engaged in dip-coating of metal parts, the mean concentration was 3.48 mg/m3 (0.8 ppm) o-xylene, 9.1 mg/m3 (2.1 ppm) m-xylene and 3.91 mg/m3 (0.9 ppm) p-xylene. The workers were also exposed to 0.8 ppm toluene and 0.9 ppm ethylbenzene. At the end of the 8 h-shift urine samples were collected and methylhippuric acid was determined. There was a linear relationship between the intensity of exposure to xylenes and the concentration of methylhippuric acid in urine. The methylhippuric acid concentration as a function of increasing xylene concentration was 17.8 mg/litre per ppm (Kawai et al., 1991a). In workers occupationally exposed to an average of 17.4 mg/m3 (4 ppm) xylene (combination of all three isomers), with a maximum of more than 430 mg/m3 (100 ppm), the urinary excretion of methylhippuric acid was linearly correlated with the air exposure (Huang et al., 1994). The urinary methylhippuric acid excretion of xylene-exposed painters at the end of the working week showed two distinct phase of excretion. Half-times for urinary excretion of methylhippuric acid were estimated to be 3.6 h for the first 10 h and 30.1 h for the next 2 days after exposure (Engström et al., 1978). A positive association between the degree of obesity and the length of half-time was seen. In volunteers exposed to m-xylene the urinary excretion of m-methylbenzoic acid was described as triphasic with half-times of 1-2, 10 and 20 h (Riihimäki et al., 1979a). The observed elimination half-time in the subcutaneous adipose tissue was about 58 h (Engström & Riikimäki, 1979). After oral administration of o-xylene (39 mg/kg body weight) maximum urinary levels of glycine and glucuronide conjugates of o-methylbenzoic acid were reported to be 33.1 and 1.0% of the administered dose, respectively. Similar values were obtained after an oral dose of 78 mg/kg body weight (Ogata et al., 1979; Ogata et al., 1980). About 4-5% of the dose absorbed in the lungs is exhaled unchanged after exposure to 870 mg/m3 (200 ppm) xylene (Sedivec & Flek, 1976, Åstrand et al., 1978, Riihimäki et al., 1979a, Riihimäki et al., 1979b). Elimination in exhaled breath is reported to follow a similar triphasic profile to that for urinary excretion of methylbenzoic acid conjugates (Riihimäki et al, 1979). An initial half-time of about one hour was obtained in a study by Campbell et al., 1988. 6.4.2 In laboratory animals Exhalation of unchanged m-xylene has been described in one study on rats. Exhalation was greatest 4 h after an intraperitoneal injection, and 13% of the dose was exhaled unchanged within 10 h (Sugihara, 1979). In mice 3.4% of the dose was exhaled within 8 h (Bergman, 1979; Bergman, 1983). In rats a total of 46% of the m-xylene dose (5 mmol/kg body weight) was excreted as m-methylbenzoic acid within 24 h, and phenobarbital (PB) treatment increased it to 70% of the dose. PB treatment increased the elimination of m-methylbenzoic acid after oral administration about 4-fold in the first 3 h, more then 2-fold in the first 12 h, and 1.5-fold within 24 h compared to untreated but m-xylene-exposed rats (Gut & Flek, 1981). Wistar rats were pretreated with PB for 3 days (80 mg/kg body weight per day) and then given m-xylene orally or intraperitoneally at a small (0.081 mmol/kg) or a large (0.81 mmol/kg) dose or by inhalation (6 h) at a low (174 mg/m3, 40 ppm) or high (1740 mg/m3, 400 ppm) concentration. PB treatment had a significant effect on the metabolism of inhaled m-xylene (decreased blood m-xylene and increased urinary excretion of m-methylhippuric acid), but only at the high dose. The PB-induced enzyme induction had an effect at both dose levels on the metabolism of orally administered m-xylene. The effect on intraperitoneally administered m-xylene was more similar to that of inhaled than that of orally administered m-xylene (Kaneko et al., 1995). After an intraperitoneal injection of 87-348 mg/kg body weight m-xylene to rats, 53-75% of the dose was excreted as m-methyl- hippuric acid in urine during 24 h (Ogata & Fujii, 1979). After an intraperitoneal dose of 319 mg/kg body weight the proportion excreted as mercapturic acids was calculated to be 10% for o-xylene and 0.6-1.3% for m- and p-xylene (Van Doorn et al., 1980). Male rats were exposed to soil-adsorbed (sandy soil or clay soil) or pure 225 µl of m-xylene containing 20 µCi of m-[14C]-xylene through the skin (Skowronski et al., 1990). The major route of excretion in the pure and sandy groups was via expired air followed by urine. However, in the presence of clay soil, the percentage of the initial dose in expired air was similar to that in urine. In the presence of clay soil, an increase in m-xylene was observed in adipose tissue. Methyl hippuric acid was the main urinary metabolite. Turkall et al. (1992) reported the bioavailability of soil-adsorbed m-xylene in male and female rats. The rats were gavaged with an aqueous suspension of 5% of gum acacia containing 150 µl of m-xylene with 5 µCi m-[14C]-xylene alone or adsorbed to sandy or clay soil. While ingested soil contaminated with m-xylene produced a higher bioavailability than the chemical alone in females, no effects of soil was observed in males. No differences in the bioavailability of m-xylene alone were observed between the sexes. m-Xylene was primarily metabolized and excreted in urine, methylhippuric acid being the main urinary metabolite in all groups. 6.5 Factors affecting toxicokinetics in humans and animals In humans, co-exposure of m-xylene and ethylbenzene and consumption of ethanol or aspirin (acetylsalicylic acid) prior to inhalation has been shown to reduce urinary excretion of one or more xylene metabolites, including methylhippuric acid (Riihimäki et al., 1982a,b; Engström et al., 1984; Campbell et al., 1988). In the case of ethanol consumption an increase in concentration of m-xylene in blood was described (Riihimäki et al., 1982a,b). Co-exposure to toluene decreased the ratio of the concentration of p-xylene in venous blood to that in exhaled air (Wallén et al., 1985). The dermal absorption of liquid m-xylene was reduced in the presence of isobutanol (Riihimäki, 1979a). Volunteers given ethanol on two evenings (total dose 137 g) preceding exposure by inhalation to either 435 or 1740 mg/m3 (100 or 400 ppm) m-xylene for 2 h enhanced the metabolism of m-xylene but only at 1740 mg/m3 (Tardif et al., 1994). Ethanol pretreatment decreased the concentration of m-xylene in blood and alveolar air during and after exposure and increased urinary excretion of m-methylhippuric acid at the end of exposure to 1740 mg/m3. Five male volunteers were exposed for 7 h/day over 3 consecutive days to 50 ppm toluene, 174 mg/m3 (40 ppm) xylene (15% o-xylene, 25% m-xylene and 60% p-xylene) or a combination of both. To study high-level exposure four men were exposed for 4 h to 95 ppm toluene or 348 mg/m3 (80 ppm) xylene or a combination of both. Mixed exposure (low-level) did not alter the concentration of the solvents in blood or exhaled air, nor did it modify the excretion of urinary metabolities. High-level mixed exposure, however, increased the concentration of solvents in blood and exhaled air and caused a delay in the urinary excretion of hippuric acid (Tardif et al., 1991). Simultaneous exposure by inhalation to toluene and xylene (15% o-xylene, 60% m-xylene and 25% p-xylene) has been studied in Sprague-Dawley rats. Exposure time was 5 h and the concentrations were 75 ppm toluene plus 979 mg/m3 (225 ppm) xylene, 150 ppm toluene plus 652 mg/m3 (150 ppm) xylene or 225 ppm toluene plus 326 mg/m3 (75 ppm) xylene. Compared to exposure to a single solvent, simultaneous exposure resulted in lower amounts of excreted urinary hippuric and methylhippuric acids over 24 h. Increased concentrations of solvents in blood and brain were found immediately post-exposure. Simultaneous exposure also enhanced the pulmonary elimination of both solvents (Tardif et al., 1992). From a toxicokinetic modelling study it was concluded that there is competitive metabolic inhibition between m-xylene and toluene in the rat (Tardif et al., 1993a). The interaction is likely to be observed when exposure exceeds 50 ppm of each solvent (Tardif et al., 1993b). Inhalation exposure of rats for 4 h to 2436 mg/m3 (560 ppm) m-xylene or 320 ppm of ethylbenzene alone, or in combination, indicated that in the combined exposure blood and brain m-xylene concentrations increased by 52 and 40%, respectively, whereas there was no corresponding effect on ethylbenzene concentrations (Frantik & Vodickova, 1995). In a study of metabolic interaction, Wistar rats were exposed for 6 h to 1305 mg/m3 (300 ppm) m-xylene, 600 ppm methyl ethyl ketone (MEK) or a mixture of both. After mixed exposure the cytochrome P-450-dependent monooxygenase activities were additively or synergistically induced. In the presence of MEK the overall metabolism of m-xylene was inhibited, as shown by an increase in xylene concentration in blood and fat and a decrease in the 24-h excretion of xylene metabolites (Liira et al., 1991). Male Wistar rats were exposed by inhalation for 4 h to 1000 mg/m3 (230 ppm) of o-xylene or 1700 ppm of acetone alone, or in combination. In the combination exposure, blood xylene immediately after the exposure was increased by 40% whereas the blood acetone level was decreased by 15%. In a corresponding study, H-strain mice were exposed for 2 h to 1392 mg/m3 (320 ppm) of o-xylene or 6655 mg/m3 (1530 ppm) of acetone alone or in combination. The combination exposure was accompanied by a 33% increase of the blood xylene concentration whereas the blood acetone level was decreased by 18% (Vodickova et al., 1995). 6.6 Biological monitoring More than 90% of xylene is transformed in human metabolism to methylhippuric acid and excreted in urine. Urinary methylhippuric acid has proved a robust measure of the amount of xylene taken up in the body over some preceding hours. The measurement has been routinely used in some countries for assessment of individual exposure to xylene in the occupational setting. About 1.5-2 g methylhippuric acid per g creatinine in the post-shift urine sample corresponds to exposure to 435 mg/m3 (100 ppm) xylene over a full workday (Lauwerys & Buchet, 1988). Different workloads cause variation in the excreted amounts of methylhippuric acid at a given exposure level since the lung uptake of xylene is directly proportional to pulmonary ventilation. Biotransformation of xylene to methylhippuric acid is inhibited in the presence of ethanol and acetylsalicylic acid (see section 6.5); these interfering factors need to be controlled when the method is applied. The analysis of xylene in blood and exhaled air can be used for assessment of exposure (Lauwerys & Buchet, 1988). These methods may be particularly suitable for estimating xylene body burden caused by the low and relatively stable background exposure in the general population, or, in case of accidental exposure, for measuring levels for a clinical toxicological evaluation. 7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS 7.1 Single exposure 7.1.1 Inhalation studies 220.127.116.11 o-Xylene The LC50 value for o-xylene in Sprague-Dawley rats (12 males/group) was calculated to be 4330 ppm (95% confidence limits 4247-4432 ppm) for a 6-h exposure. The reported signs of intoxication were hypotonia and somnolence. Autopsy on surviving animals 14 days later revealed no macroscopic lesions of lung, liver or kidneys (Bonnet et al., 1982). Under similar conditions the LC50 value for mice (OF-1) was 4595 ppm (4468-4744 ppm) (Bonnet et al., 1979). Rats (probably Wistar, sex not stated, 10 animals/group) were exposed to 1531, 3062 or 6125 ppm for 24 h. No deaths occurred at 1531 ppm, one death at 3062 ppm and 8 deaths at 6125 ppm (Cameron et al., 1938). In the same study one group was exposed to 12 250 ppm o-xylene for 12 h. Two deaths occurred, one after 2 h. Autopsy of those animals that died did not reveal any macroscopic or microscopic lesions in the organs studied (Cameron et al., 1938). In the same study mice (10 animals/group) were exposed to the same concentrations for the same period of time as the rats. There were no deaths at 1531 ppm, four deaths at 3062 ppm and nine deaths at 6125 ppm. In the group exposed to 12 250 ppm for 12 h there were two deaths, one after 9 h. The organs of animals that died after exposure showed no characteristic changes (Cameron et al., 1938). In a study of the effect on prenarcotic motor behaviour, groups of eight male rats (CFY) were exposed to o-xylene (dose not stated) for 1, 2, 3 or 4 h. No significant effects on group motor activity were observed. Narcosis occurred at higher concentrations with a threshold of 2180 ppm for a 4-h exposure (Molnar et al., 1986). Mice (strain, sex and numbers not stated) were exposed for 2 h to o-xylene in order to determine the minimum concentration needed for an animal to fall on its side and die. The minimum concentration for falling was 3400-4600 ppm and for death 6900 ppm (Lazarew, 1929). In a study of subnarcotic effects of solvents in Wistar rats and H-strain mice, using electrically evoked seizures, the lowest effective concentration of o-xylene was 170 ppm. The criterion used was a significant suppression by 10% of the generation and maintenance of the seizure discharge after 4 h (rats) or 2 h (mice) of inhalation (Frantik et al., 1994). A 30% suppression was induced by o-xylene at a concentration of 390 ppm, corresponding to a blood concentration of 62 µmol/litre (Frantik et al., 1993). In order to determine the RD50 value (exposure level reducing the respiratory rate by 50%), groups of male mice (OF-1) were exposed to o-xylene. The RD50 value was calculated to be 1467 ppm (1406-1530 ppm). The onset of response was rapid and the maximum decrease in respiratory rate was reached within a few minutes (De Ceaurriz et al., 1981). In a study of conditioned behaviour in mice, an increased response rate was observed after a 30-min exposure to 1400-2000 ppm o-xylene. At higher concentrations there was a decrease in response rate with an EC50 of 5179 ppm. The biphasic response indicates that there was excitation of the central nervous system at low concentrations and depression at higher concentrations (Moser et al., 1985). In a study to observe effects in the "behavioural despair" swimming test, groups of 10 mice (OF-1) were exposed to 0, 1010, 1101, 1207 or 1234 ppm o-xylene for 4 h. The ID50 (50% decrease in immobility) value was calculated to be 1127 ppm (1068-1182 ppm) (De Ceaurriz et al., 1983). The study demonstrated subnarcotic effects by o-xylene on the CNS. 18.104.22.168 m-Xylene After a 6-h exposure to m-xylene the LC50 in rats and mice was reported to be 5984 ppm (5796-6181 ppm) and 5267 ppm (5025-5490 ppm), respectively (Bonnet et al., 1979; Bonnet et al., 1982). The signs of toxicity consisted of hypotonia, somnolence, narcosis, and clonic spasms leading to death due to respiratory failure (Lazarew, 1929; Cameron et al., 1938, Bonnet et al., 1982; Moser et al., 1985; Molnar et al., 1986). In the comparative study by Frantik et al., (1994) described in section 22.214.171.124, the lowest effective air concentration for m-xylene was 210 ppm. A biphasic CNS response occurred at similar exposure levels to those seen for o-xylene (section 126.96.36.199) (Moser et al., 1985). The narcotic threshold in rats of about 2100 ppm m-xylene determined in prenarcotic behaviour studies was similar to that observed for o-xylene (Molnar et al., 1986). During a 4-h exposure to 8000 ppm m-xylene, 10 out of 12 rats (Carwoth-Wistar) died (Smyth et al., 1962). When groups of rats (Wistar; 6 males/group) were exposed for 24 h to 0, 75, 150 or 300 ppm m-xylene, there was a significant decrease in cytochrome P-450 concentrations at all doses, and a dose-related decrease in 7-ethoxycoumarin-O-deethylase activity in the lung. No abnormalities of the lungs, as determined by scanning electron microscopy, were seen in two animals exposed to 300 ppm (Elovaara et al., 1987). When male Wistar rats were exposed for 4 h to a 1:1 mixture of m-xylene and n-butyl alcohol or to the single substances at 500-4000 ppm, there were disturbances of rotarod performance. The medial effective concentrations (EC50) were calculated to be 3080 ppm (mixture), 6530 ppm ( n-butyl alcohol) and 1980 ppm (xylene) respectively. The combined exposure gave less than additive effects (Korsak et al., 1993). A concentration-dependent decrease in respiratory rate in mice was demonstrated in a study where mice were exposed to 500-4000 ppm of n-butyl alcohol, m-xylene or a 1:1 mixture of both. The RD50 was calculated to be 3010 ppm, 1360 ppm and 3140 ppm, respectively. The combined exposure gave less than additive effects (Korsak et al., 1993). The acute neurobehavioural effect of m-xylene was evaluated after 20 min inhalation exposure using a functional observations battery in mice. In the concentration range of 2000-8000 ppm, these effects included changes in posture, decreased arousal and rearing, increased ease of handling, disturbances of gait, mobility and righting reflex, decreased forelimb grip strength, increased landing foot splay and impaired psychomotor coordination. The response to various sensory stimuli was also decreased. These acute effects were short-lived, recovery beginning within minutes of removal from the exposure chamber (Tegeris & Balster, 1994). 188.8.131.52 p-Xylene A 4-h LC50 value in rats (female Sprague-Dawley) of 4740 ppm p-xylene has been reported (Drew & Fouts, 1974). The corresponding 6-h value was 4591 ppm (4353-5049 ppm) (Bonnet et al., 1982), and for mice (OF-1) was 3907 ppm (3747-4015 ppm) (Bonnet et al., 1979). The signs of toxicity were similar to those reported for the other two isomers. Like the other two isomers, exposure to p-xylene gave a biphasic CNS response (Moser et al., 1985). In another study (Molnar et al., 1986), marked activation and tremor were observed at concentrations between 400 and 1500 ppm p-xylene in rats. The narcotic threshold was 1940 ppm. When Sprague-Dawley rats (16 females/group) were exposed for 4 h to 0, 1000, 1500 or 2000 ppm p-xylene, a dose-dependent increase in serum enzymes activites was observed. This was taken as a sign of hepatocellular and hepatobiliary damage (Patel et al., 1979). In other studies at higher exposure levels, no microscopic hepatic lesions were seen in rats or mice (Cameron et al., 1938; Furnas & Hine, 1958; Bonnet et al., 1982). When Long Evans rats were exposed for 4 h to 0, 800 or 1600 ppm p-xylene, the flash-evoked potential of the visual system was reduced at the highest exposure level (Dyer et al., 1988). The authors suggested that this may have been secondary to changes in arousal or excitability. In a study of the effect on learning tasks and motor activity, rats (Long Evans) were exposed to 0 or 1600 ppm p-xylene for 4 h. Signs of toxicity (unsteadiness and fine tremor) disappeared 30 min post-exposure. The results indicate an effect on motor control rather than on cognitive capacity (Bushnell, 1989). In the comparative study by Frantik et al. (1994) described above (section 184.108.40.206), where rats and mice were exposed, the lowest effective air concentration for p-xylene was 220 ppm. After a 4-h exposure to 1000 ppm p-xylene there was a decrease in pulmonary cytochrome P-450 in rabbits and a decrease in NADPH-cytochrome c-reductase and mixed-function oxidase activity in rats (Patel et al., 1976; Patel et al., 1978). When Sprague-Dawley rats were exposed to 3400 ppm p-xylene for 4 h and killed 12 h later, an induction of cytochrome P-450 activities (CYP2B) in liver microsomes was observed. On the other hand, the pulmonary cytochrome P-450 activities were inhibited (Day et al., 1992). In rats (Sprague-Dawley) p-xylene (2800 ppm for 4 h) has been shown to potentiate hepatotoxicity induced by bromobenzene, while the effect of bromobenzene on pneumotoxicity was unaffected by p-xylene, indicating differences in xylene metabolism between the liver and the lung (Day et al., 1992). 220.127.116.11 Technical or undefined xylene In rats LC50 values of 6350, 6700 and 10 950 ppm have been reported after 4-h exposure (Hine & Zuidema, 1970; Carpenter et al., 1975; Lundberg et al., 1983). Deaths occurred during the exposure period. No LC50 values for mice have been found, although experiments have been carried out at up to 7000 ppm for 30 min (Moser et al., 1985). Signs of toxicity were the same as those produced by the individual isomers. No signs of toxicity were reported when rats and dogs were exposed for 4 h to 580 and 530 ppm, respectively. The composition was 7.63% o-xylene, 65.01% m-xylene, 7.84% p-xylene and 19.27% ethylbenzene (Carpenter et al., 1975). The same type of response at similar exposure levels as for the three individual isomers was observed in mice in a conditioned behavioural study (Moser et al., 1985). In rats effects of xylene were studied on an operant behaviour maintained by a fixed-ratio liquid reinforced schedule. A decrease in the reinforcement rate was seen after exposure to 113 ppm for 2 h (Ghosh et al., 1987; Ghosh & Pradhan, 1987). When rats (Fischer F-344) were exposed to 1450 ppm xylene for 8 h, a slight increase in the auditory response threshold at 20 kHz was noted (Pryor et al., 1987). The xylene composition was 10% o-xylene, 80% m-xylene and 10% p-xylene. In mice (Swiss-Webster) exposed to 1300 ppm xylene for one minute, a decrease in respiratory rate as an indication of respiratory tract irritation was seen (Carpenter et al., 1975). This effect was not seen at an exposure level of 460 ppm. No histological abnormalities were seen on histological examination of livers from rats exposed to 5480 ppm for 4 h, nor were there any changes in serum activities of an indicator enzyme (sorbitol dehydrogenase) for hepatotoxicity after exposure to > 340 ppm (Lundberg et al., 1986). No histological abnormalities were seen in cat livers after exposure to about 9500 ppm for up to 2 h (Carpenter et al., 1975). In dogs (Beagle) 1200 ppm xylene for 4 h caused lacrimation but there was no noticeable effect at 530 ppm (Carpenter et al., 1975). When groups of cats (five animals/group) were exposed for 5740, 6900 or 9200 ppm for up to 6 h, there was a concentration-dependent decrease in time to onset of staggering and mild narcosis. There was, however, a large individual variation. Deep narcosis was seen in four animals at 9200 ppm xylene (Engelhardt & Estler, 1935). 7.1.2 Other exposure routes The oral LD50 values in rat have been reported to be 3608 mg/kg body weight for o-xylene, 5011 mg/kg body weight for m-xylene and 4029 mg body weight for p-xylene (Smyth et al., 1962). For various mixtures of xylenes oral LD50 values in rat have been reported to be between 3523 and 8700 mg/kg body weight (Wolf et al., 1956; Hine & Zuidema, 1970; NTP, 1986). In mice the corresponding values were reported to be 5627 mg/kg body weight for male and 5251 mg/kg body weight for females (NTP, 1986). Signs of toxicity at lethal doses were CNS depression and congestion of cells in liver, kidney and spleen, seen by histological examination. A dermal LD50 value for rabbits (New Zealand White) of 12 180 mg/kg has been reported for a 24-h exposure to m-xylene (Smyth et al., 1962). From studies with intraperitoneal (i.p.), intravenous (i.v.), subcutaneous (s.c.) and intramuscular (i.m.) administration in rats and mice the acute toxicity of xylene is low (Bell et al., 1992). All three isomers have been found to interfere with the modulation of the vestibular-oculomotor pathways in the rat. The blood threshold levels for this effect were 170-200 µg/ml following administration by the i.v. route (Tham et al., 1984). Similar effects have also been reported for m-xylene in rabbit. The vestibular-oculomotor effects were seen at blood levels of 30 µg/ml and some deaths due to respiratory stress were recorded at 100 µg/ml (Larsby et al., 1976; Aschan et al., 1977; Ödkvist et al., 1979; Ödkvist et al., 1980). A dose-dependent depletion of hepatic glutathione, following i.p. administration, has been demonstrated in rats. With o-xylene the effect was seen from 50 mg/kg and with the other two isomers from 425 mg/kg (Van Doorn et al., 1980). A decrease in pulmonary cytochrome P-450 levels has been observed with the three isomers, when administered (i.p.) at 531 mg/kg (Pyykkö et al., 1987). The CYP2B1 and CYP1A1 isoenzyme activities, benzyloxy-resorufin O-deethylation and ethoxyresorufin O-deethylation, respectively, were studied in nasal, pulmonary and hepatic tissues of rats injected intraperitoneally with m-xylene. Tissues taken at 2, 12 and 24 h after injection showed inhibition of these activities in both nasal and pulmonary microsomes, but increased activities in hepatic microsomes (Blanchard & Morris, 1994). The effects of intraperitoneal administration of o-xylene (1g/kg body weight) on: (a) rat hepatic and pulmonary mixed-function oxidase content and activity; and (b) microsomal membrane structural parameters were studied 1, 3, 6 and 12 h after administration (Park et al., 1994). The pulmonary cytochrome P-450 content and aryl hydrocarbon hydroxylase activity were decreased, a maximal inhibition occurring 3 h after dosing. Reduced pulmonary activity for both ethoxyresorufin O-dealkylation and benzyloxyresorufin O-dealkylation was noted. In contrast, increased hepatic cytochrome P-450 content was noted, with slightly increased ethaxyresorufin O-dealkylation and markedly increased benzyloxyresorufin O-dealkylation. An increase in pulmonary microsomal phospholipid content and cholesterol content was noted even 1 h after dosing. In liver the phospholipid content increased although there was no change in cholesterol content; this suggested an increase in membrane fluidity. Sprague-Dawley rats were given m-xylene (1 g/kg body weight) intraperitoneally and killed one hour after treatment. Microsomes from the lung were then prepared. Compared to controls, m-xylene administration decreased the CYP2B1 activity but did not alter the CYP1A1 activity or epoxide hydrolase activity. In total, m-xylene administration resulted in an inhibition of benzo (a)pyrene detoxication and increased production of toxic metabolites in the pulmonary microsomal preparations (Stickney et al., 1991). Xylenes have been shown to inhibit the hypotonic haemolysis of erythrocytes in vitro at low concentrations. The EC50 values were 29, 39 and 44 µg/ml for o-xylene, m-xylene and p-xylene, respectively (Holmberg et al., 1974). 7.2 Short-term exposure 7.2.1 Inhalation studies 18.104.22.168 o-Xylene In a study on the noradrenaline and dopamine levels in various parts of the forebrain and hypothalamus, Sprague-Dawley rats (six males/group) were exposed to 0 or 2000 ppm o-xylene 6 h/day for 3 days. The animals were killed within 18 h after final exposure. There was a significant increase in catecholamine levels and turnover in various parts of the hypothalamus and a decrease in the dopamine turnover in the forebrain of exposed animals (Andersson et al., 1981). In order to study the effects on cytochrome P-450 and enzyme activities Sprague-Dawley rats (four males/group) were exposed to 0 or 2000 ppm o-xylene, 6 h/day for 3 days. There was a significant increase in relative liver weight and cytochrome P-450 content in exposed animals. Furthermore, there were increases in some liver enzyme activities. In lungs, there was a decrease in cytochrome P-450 activity (Toftgård & Nilsen., 1982). When guinea-pigs (15 per group) were exposed to 0 or 780 ppm o-xylene, 8 h/day, 5 days/week for 6 weeks, there was a marked decrease in body weight gain in exposed animals. No effects on the liver, kidney, heart, spleen or lung were observed upon histological examination (Jenkins et al., 1970). In the same study beagle dogs were exposed for the same period of time. One dog out of two experienced tremors throughout the exposure period. No other signs of toxicity were reported (Jenkins et al., 1970). Squirrel monkeys were also exposed in the same manner. One monkey out of three died on day seven. No other signs of toxicity were reported (Jenkins et al., 1970). 22.214.171.124 m-Xylene In a study of levels of noradrenaline and dopamine in various parts of the forebrain and hypothalamus, Sprague-Dawley rats (six males/group) were exposed to 0 or 2000 ppm m-xylene, 6 h/day for 3 days. The animals were killed within 18 h after the last exposure. A significant increase in catecholamine levels and turnover was observed in various parts of the hypothalamus of exposed animals. There was no effect on dopamine levels (Andersson et al., 1981). In another study, Sprague-Dawley rats (four males/group) were exposed to 0 or 2000 ppm m-xylene for 3 days. The effect on cytochrome P-450 and enzyme activities in liver, kidney and lung were studied. In exposed animals there was a significant increase in relative liver weight, in cytochrome P-450 content in liver and kidney, and in some enzyme activities in these two organs. The content of pulmonary cytochrome P-450 was decreased (Toftgård & Nilsen, 1982). In a study of the effect on xenobiotic metabolism in Wistar rats, 10 males per group were exposed to 0, 50, 400 or 750 ppm m-xylene, 6 h/day, 5 days/week for one week. At the two highest doses there was a significant increase in hepatic microsomal protein and NADPH-cytochrome c reductase levels, and a decrease in hepatic glutathione levels. There was no effect on hepatic cytochrome P-450 levels or on renal glutathione levels. At all dose levels there was a significant increase in renal cytochrome P-450 and some enzyme activities. When the animals were exposed to the same regimen for 2 weeks similar results were obtained. There were no abnormalities upon histological examination of the liver (Elovaara, 1982). When Wistar rats (20 males/group) were exposed to 0 or 300 ppm m-xylene 6 h/day, 5 days/week for one week there was, in exposed groups, a significant increase in hepatic and renal 7-ethoxycoumarin O-deethylase activity and in renal UDP-glucuronyl transferase. When exposure time was 2 weeks there was also a significant increase in hepatic cytochrome P-450 and NADPH-cytochrome c reductase activities (Elovaara et al., 1982). In order to study the effect on lung cytochrome P-450 in rats, six male Wistar rats/group were exposed to 0 or 300 ppm m-xylene 7 h/day, 4 days/week for 5 weeks. The only effects seen were a significant decrease in cytochrome P-450 content and 7-ethoxycoumarin O-deethylase activity (Elovaara et al., 1987). When the effects on cerebral biochemistry was studied, groups of Wistar rats (15 males/group) were exposed to 0, 50, 400 or 750 ppm m-xylene 6 h/day, 5 days/week for 1 or 2 weeks. The only effect seen after one week of exposure was a significant decrease in glutathione levels at all concentrations. After 2 weeks there were also a dose-dependent decrease in superoxide dismutase activity, a significant increase in NADPH-diaphorase activity at all concentrations and a significant increase in azoreductase activity at the two highest concentrations (Savolainen & Pfäffli, 1980). 126.96.36.199 p-Xylene In a study of levels of noradrenaline and dopamine in the forebrain and hypothalamus, Sprague-Dawley rats (six males/group) were exposed to 0 or 2000 ppm p-xylene 6 h/day for 3 days. The animals were killed 16-18 h after the last exposure. In exposed animals there was a significant increase in catecholamine levels and turnover in various parts of the hypothalamus. There was no effect on dopamine levels or turnover in the forebrain (Andersson et al., 1981). In order to study the effect on cytochrome P-450 and enzyme activities in the liver, kidney and lung, Sprague-Dawley rats (four males/group) were exposed to 0 or 2000 ppm 6 h/day for 3 days. In exposed animals there were significant increases in relative liver weight, in hepatic cytochrome P-450 content, in NADPH-cytochrome c reductase activity in the liver and kidney, and in 7-ethoxyresorufin O-deethylase activity in the kidney. There was also a decrease in pulmonary cytochrome P-450 content (Toftgård & Nilsen, 1982). To study the lung microsomal activity, rabbits (New Zealand White; four males/group) were exposed to 0 or 1000 ppm p-xylene 4 h/day for 2 days. In exposed animals there was a significant decrease in microsomal cytochrome P-450 concentration and in NADPH-cytochrome c reductase activity (Patel et al., 1978). Inhibition of CYP2B1 has been observed in the lungs of rats dosed with p-xylene (Verschoyle et al. 1993). Rats exposed to 300 ppm p-xylene, 6 h/day for 1, 3 or 5 days exhibited alterations in pulmonary microsomal membrane structural and metabolic parameters (Silverman & Schatz, 1991). Following 1 day of exposure, conjugated diene levels were elevated while total phospholipid levels, cytochromes P-450 content, benzyloxyresorufin O-dealkylase activity and 2-aminofluorene N-hydroxylase activity were decreased. Core membrane fluidity was increased following 3 days of exposure. After 5 days of exposure all parameters returned to control levels with the exception of aryl hydrocarbon hydroxylase activity, which was increased by 41%. Extracellular surfactant levels were also decreased after 1 and 3 days of exposure but returned to control values after 5 days. The increase in aryl hydrocarbon hydroxylase activity after 5 days of exposure could have important consequences on the metabolism of co-administered xenobiotics. Male Fischer-344 rats exposed to 0 or 1600 ppm p-xylene by inhalation, 6 h/day, for 1 or 3 days did not produce overt hepatotoxicity but resulted in a significant increase in the concentration of hepatic cytochrome P-450 (Simmons et al., 1991). However, the concentration of hepatic cytochrome P-450 had returned to control levels within 2 to 3 days after exposure. p-Xylene has been shown to decrease axonal transport of proteins and glycoproteins in rats (Long-Evans) exposed by inhalation to 1600 ppm for 6 h/day, 5 days/week, for 8 days. When ethanol (10% in drinking-water) was given during 6 days prior to inhalation of p-xylene, the treatment prevented the decreased axonal transport. Ethanol per se did not decrease the axonal transport (Padilla et al., 1992). When 10 Wistar rats and 10 mice (strain not given) were exposed to 1226 ppm p-xylene 8 h/day for 14 days, no animals died. No other results were reported (Cameron et al., 1938). When mice were exposed to 1200 ppm p-xylene 6 h/day for 4 days and infected with a sublethal dose of murine cytomegalovirus, 34% mortality occurred, whereas no deaths occurred among uninfected, p-xylene-exposed mice or infected, air-exposed mice (Selgrade et al., 1993). Although p-xylene potentiated liver damage caused by the virus, the magnitude of serum enzyme activities indicated that this damage was not the probable cause of death. Enhanced mortality was related to enhanced xylene toxicity due to suppression of cytochrome P-450, although additive or synergistic damage to tissues other than liver could not be ruled out. There was no indication that p-xylene had caused immune suppression. 188.8.131.52 Technical or undefined xylene When rats (strain not defined) were exposed to 620, 980 or 1600 ppm xylene 18-20 h/day for 7 days, instability, incordination and narcosis were observed at the two highest concentrations. Signs of mucous membrane irritation occurred, and congestion and cloudy swelling of kidneys was reported at 980 ppm (Batchelor, 1927). Similar results were reported in another study (Winslow, 1927). Groups of Harlan-Wistar rats (25 males/group) were exposed to 0, 180, 460 or 810 ppm xylene 6 h/day, 5 days/week for 13 weeks. The xylene consisted of 7.63% o-xylene, 65.01% m-xylene, 7.84% p-xylene and 19.27% ethylbenzene. At 3, 7 and 13 weeks 3, 3 and 4 animals, respectively, were killed. No treatment-related histopathology was seen (Carpenter et al., 1975). In a study of levels of noradrenaline and dopamine in the forebrain and hypothalamus of rats, the xylene mixture used was 2.0% o-xylene, 64.5% m-xylene, 10.0% p-xylene and 23.0% ethylbenzene. Sprague-Dawley rats (6 males/group) were exposed to 0 or 2000 ppm xylene 6 h/day for 3 days. The animals were killed 16-18 h after the last exposure. There was a significant increase in catecholamine levels and turnover in the hypothalamus and a significant increase in dopamine levels and turnover in the forebrain (Andersson et al., 1981). In order to study the effect on levels of neurotransmitters in the rat brain, five to six Sprague-Dawley rats/group were exposed to 0, 200, 400 or 800 ppm xylene (mixture not defined) for 30 days. Acetylcholine levels in the striatum were decreased at > 400 ppm. Noradrenaline levels in the hypothalamus were increased significantly at the highest dose. From 400 ppm the cAMP levels were decreased in the striatum, and at 800 ppm the glutamine levels in the midbrain were increased. At all concentrations glycine and GABA levels in the midbrain were increased (Honma et al., 1983). When 12 male Fischer F-344 rats/group were exposed to 0 or 1450 ppm xylene 8 h/day for 3 days, there was, in exposed animals, an increase in the auditory response threshold at 12 and 20 kHz. Rats (Long Evans) were exposed to 2500 ppm of mixed xylenes 6 h/day for 5 days. Testing of auditory function was conducted 5 to 8 weeks after exposure using reflex modification audiometry (RMA). The results indicated increased RMA thresholds for the mid-frequency tones (e.g., 8, 16 and 24 kHz) but not for higher or lower tones (Crofton et al., 1994). In another study Sprague-Dawley rats (four males/group) were exposed to 0 or 630 ppm xylene 6 h/day, 5 days/week for 4 weeks. The animals were killed the morning after the last exposure. In exposed animals there was a significant decrease in body weight gain, while the absolute and relative liver weights were increased. There was an increase in hepatic cytochrome P-450 and the xylene was shown to act as a phenobarbital-like inducer of cytochrome P-450. The xylene used was 2.0% o-xylene, 64.5% m-xylene, 10.0% p-xylene and 23.0% ethylbenzene (Toftgård et al., 1981). When male Sprague-Dawley rats (8-12 animals/group) were exposed to 0, 75, 250, 500, 1000 or 2000 ppm xylene 6 h/day for 3 days there was a dose-dependent increase in the concentration of liver microsomal cytochrome P-450. When animals were exposed to the two highest concentrations for 5 days, there was a dose-dependent increase in the surface area of smooth endoplasmic reticulum but not in rough endoplasmic reticulum. Based on their results the authors concluded that xylene causes phenobarbital-type induction in the liver. The xylene used was the same as that in the previous paragraph (Toftgård et al., 1983). The same type of xylene was also used in a study where four male Sprague-Dawley rats/group were exposed to 0 or 2000 ppm xylene 6 h/day for 3 days. In exposed animals there were significant increases in hepatic and renal cytochrome P-450 content, in NADPH-cytochrome c reductase activities and 7-ethoxyresorufin O-deethylase activities in liver and kidney. The pulmonary cytochrome P-450 content was decreased. Increased enzyme activity in liver and kidney and decreased activity in the lung were thus observed (Toftgård & Nilsen, 1982). Groups of male Wistar rats (20 animals/group) were exposed to 0 or 300 ppm xylene 6 h/day, 5 days/week for up to two weeks. In each group 10 animals had 15% v/v ethanol in the drinking-water. There was a significant decrease in motor activity in exposed animals. In addition, there was a significant increase in brain DT-diaphorase activity, in acid proteinase and in hepatic and renal 7-ethoxycoumarin O-deethylase activities. Concurrent dosing with ethanol had a marked synergistic effect on hepatic and renal 7-ethoxycoumarin O-deethylase activities. The xylene used was 80% m-xylene and 12% p-xylene (Savolainen et al., 1979a,b). In a study of the effect of simultaneous exposure to xylene (undefined) and noise on metabolic activity in the myocardium, male rats (strain not specified) were exposed to 0 or 69 ppm xylene 4 h per day, 5 days per week for 6 weeks, and simultaneously to a noise level of 0, 46, 85 or 95 dB. There were changes in some enzyme activities, but the brief reporting makes the study impossible to evaluate (Ivanovich et al., 1985). When Beagle dogs (four males per group) were exposed to 0, 180, 460 or 810 ppm xylene 6 h per day, 5 days per week for 13 weeks, no treatment-related effects were reported. The xylene used was 7.63% o-xylene, 65.01% m-xylene, 7.84% p-xylene and 19.27% ethylbenzene (Carpenter et al., 1975). 7.2.2 Other exposure routes Decreased body weight compared to controls was noted in rats (Sprague-Dawley) administered orally 1062 mg m-xylene/kg body weight for 3 days (Pyykkö, 1980), and reduced terminal body weight was observed in rats (Fischer F-344) administered 500 mg m-xylene/kg body weight, 5 days per week, for 4 weeks (Halder et al., 1985). Three days administration of 1062 mg m-xylene/kg body weight resulted in significant increases in liver weight, liver cytochrome P-450 and cytochrome b5 levels and NADPH cytochrome c reductase and MFO enzymes activities. The same range of increases was also seen in the kidney (Pyykkö, 1980). In another study, however, there were no effects on kidney weight and no treatment-related abnormalities histopathologically in Fischer rats given 500 or 2000 mg/kg body weight 5 days per week for 4 weeks (Dési et al., 1967). Upon oral administration of 0, 125, 250, 500, 1000 or 2000 mg xylene per kg body weight to rats (F-344/N), in a 14-day study, a high mortality was seen in the highest dose group. The xylene used was 9.1% o-xylene, 60.2% m-xylene, 13.6% p-xylene and 17.0% ethylbenzene. The body weight gain was reduced in males at > 250 mg/kg body weight and in females at 125 mg/kg body weight and > 1000 mg/kg body weight. There were no treatment-related abnormalities at gross necropsy (NTP, 1986). In the same study xylene was administered at 0, 62.5, 125, 250, 500 or 1000 mg per kg body weight, 5 days per week, for 13 weeks. No treatment-related abnormalities were seen during gross necropsy or histopathological examination (NTP, 1986). Daily administration (s.c.) of xylene (undefined) for up to 4 weeks to rats (strain not given) resulted in significant mortality at 870 mg/kg body weight but not at 435 or 174 mg/kg body weight. Repeated administration of 435 mg/kg body weight resulted in decreased learning rate (Dési et al., 1967). When Sprague-Dawley rats were given 0 or 3123 mg/kg body weight for 3 days, there was a significant increase in liver weight, cytochrome P-450 levels, NADPH cytochrome c reductase and activity of MFO enzymes. The xylene used was 30% o-xylene, 55% m-xylene and 15% p-xylene (Pathiratne et al., 1986). In order to study further the effects of p-xylene, rats were given p-methylbenzyl alcohol (PMBA) or 2,5-dimethylphenol (DMP) (300 mg/kg body weight and 150 mg/kg body weight, respectively) intraperitoneally once a day for 3 days. It was concluded that of the two metabolites, PMBA may have a significant role in the inhibition of pulmonary cytochrome P-450 caused by p-xylene (Day & Carlson, 1992). Male Sprague-Dawley rats (n=10) were given xylene (isomer not stated) intraperitoneally, as a single dose per day, for 3 consecutive days. The dose given was equal to half the LD50 (1.6 ml/kg body weight per day). Only slight somnolence was observed. After the last dosing the animals were killed and aminopeptidase activities in several regions of the brain were measured. The activities were largely unaffected, compared to those of controls (De Gandarias et al., 1993). Brain cell cultures enriched in astroglial cells were prepared from neonatal Sprague-Dawley rats. The cultures were exposed for 1 h to 3, 6 or 9 mmol o-xylene/litre. The ATPase activity was reduced in a dose-dependent manner (Naskali et al., 1994). 7.3 Long-term exposure A short summary of long-term studies is presented in Table 6. In Wistar rats exposed to 1000 ppm m-xylene for 6 h/day, 5 days/week for 3 months or to 100 ppm for 6 months, slight ultrastructural changes (proliferation of smooth endoplasmic reticulum) were found in hepatocytes. When rats were exposed to a 1:1 combination of m-xylene and toluene (500 plus 500 ppm or 50 plus 50 ppm), the changes were a combination of those of each single solvent (Rydzynski et al., 1992). The combined exposure at both exposure levels gave more pronounced disturbances in a rotarod performance test and decrease in spontaneous motor activity compared to single solvent exposure. In animals exposed to 500 plus 500 ppm for 3 months a decrease in red blood cell count and an increase in rod neutrophil cell count were observed (Korsak et al., 1992). In a six-week study, groups of rats (Sprague-Dawley or Long-Evans; 15 animals/group) were exposed to 0 or 780 ppm o-xylene (8 h/day, 5 days/week) or to 78 ppm continously for 90 days. There was no effect on body weight gain, leukocyte count, haemoglobin level or heamatocrit. Histological examination of the liver, kidney, heart, spleen and lung revealed no effects (Jenkins et al., 1970). Table 6. Effects of xylenes in long-term studies Compound Species Exposure NOEL LOEL End-point Reference (ppm) (ppm) Inhalation exposure o-Xylenea rat, dog, 13 weeks 780 - Jenkins et al., 1970 guinea-pig o-Xylenea monkey 13 weeks + 78 - Jenkins et al., 1970 m-Xylenea rat 3 months - 1000 liver cell changes (i.e. inc. smooth Rydzynski et al., 1992 endoplasmic reticulum, lysosomes) m-Xylenea rat 6 months - 100 liver cell changes (i.e. inc. smooth Rydzynski et al., 1992 endoplasmic reticulum, lysosomes) m-Xylenea rat 3 months - 100 dec. lymphocyte/monocyte count; Korsak et al., 1992 dec. rotorod, performance m-Xylenea rat 6 months - 100 dec. rotorod, performance Korsak et al., 1992 dec. spontaneous motor activity Xylenes rat 3 months 50 100 dec. rotorod performance Korsak et al., 1994 dec. spontaneous motor activity Xylenes rat 6 months 346 923 liver effects (inc. liver weight inc. Ungvary, 1990 smooth endoplasmic reticulum, inc. P-450 activity) Table 6. (Cont'd) Compound Species Exposure NOEL LOEL End-point Reference (ppm) (ppm) Inhalation exposure Xylenes rat 13 weeks 810 - Carpenter et al., 1975 Xylenes dog 13 weeks 810 - Carpenter et al., 1975 Xylenes rat 6 weeks - 800 ototoxicity Pryor et al., 1987 (14h/day) Xylenes rat 61 days - 1000 ototoxicity Nylen & Hagman, 1994 (18 h/day) Xylenes rat 18 weeks - 300 liver microsomes activity Elovaara et al., 1980 Xylenes rat 18 weeks - 300 brain superoxide dismutase activity Savolainen et al., 1979 Xylenes rat 13 weeks + - 320 brain lipid composition changes Kyrklund et al., 1987 Xylenes gerbil 3 months 160 320 change in astroglial cell marker Rosengren et al., 1986 proteins Table 6. (Cont'd) Compound Species Exposure NOEL LOEL End-point Reference (ppm) (ppm) Oral exposure Xylenes rat 13 weeks 1000 - NTP, 1986 Xylenes mouse 13 weeks 2000 - NTP, 1986 Xylenes rat 13 weeks - 150 increased liver weights (males); Condie et al., 1988 hyaline droplet nephropathy (males) Xylenes rat 2 years 250 500 mortality NTP, 1986 Xylenes mouse 2 years 500 - NTP, 1986 a Only one dose was used b Continous exposure The effects of combined exposure to m-xylene and n-butyl alcohol have been studied in rats exposed to the individual solvents at 50 and 100 ppm and their 1:1 mixture at 50 plus 50 ppm and 100 plus 100 ppm, 6 h/day, 5 days/week for 3 months (Korsak et al., 1994). The results indicate less than an additive toxic effect (motor coordination disturbances) of combined exposure to m-xylene and n-butyl alcohol. For xylene alone an effect was seen at 100 ppm but not at 50 ppm. Rats (CFY) were exposed to xylene (10% o-xylene, 50% m-xylene, 20% p-xylene and 20% ethylbenzene) for 8 h/day up to 6 months at concentrations of 600, 1500 or 4000 mg/m3. No macroscopic changes were seen but the relative liver weight was increased at 4000 mg/m3. At 4000 mg/m3 hypertrophy of the centrilobular zone in the liver, including a change in the amount of smooth and rough endoplasmic reticulum, was seen. As a result of xylene exposure the hexobarbital sleeping time decreased. Liver enzymatic activities were increased during the first 6 weeks. After the 4-week exposure-free period the changes described above could no longer be seen. The same type of changes could also be seen when xylene was applied orally, subcutaneously or intraperitoneally for a short period of time (4-7 day). Essentially the same changes as those described for rat liver were also seen in livers from mice and rabbits (Ungvary, 1990). Groups of 50 male and 50 female Fischer-344/N rats received 0, 250 or 500 mg xylene/kg body weight. The xylene used was 9.1% o-xylene, 60.2% m-xylene, 13.6% p-xylene and 17.0% ethylbenzene. The doses were given (in corn oil) by stomach tube on 5 days per week for 103 weeks. The animals were killed within 14 days after the last dosing. Body weights of high-dose (500 mg/kg body weight) males were 5 to 8% lower than those of vehicle controls. Results for low-dose males and both female groups were comparable to those of controls. Gross observation and histopathological results showed no incidences of non-neoplastic effects in dosed groups, related to the administration of xylene, at any sites (NTP, 1986; Huff et al., 1988). In the same study groups of 50 male and 50 female B6C5F1 mice received 0, 500 or 1000 mg xylene/kg body weight. The same type of technical xylene was used. The doses were given, in corn oil, by stomach tube 5 days per week for 103 weeks, after which the animals were killed within 14 days. No significant difference in mean body weights or survival was observed between treated animals and controls. Gross observation and histopathological results indicated that at no site were the incidences of non-neoplastic effects in dosed groups related to the administration of xylene (see also section 7.7). Male Fischer-344 rats were exposed to 0, 800, 1000 or 1200 ppm xylene 14 h/day, 7 days/week for 6 weeks. At the highest dose level there was a slight impairment of auditory (but not of visual or somatosensory) conditioned avoidance response. All animals had increased auditory response thresholds compared to controls at the same frequencies. At 1000 and 800 ppm the thresholds were elevated at 16 kHz and 8 kHz and at 1200 ppm the brainstem auditory-evoked response thresholds were elevated at 4, 8 and 16 kHz tone frequency. The xylene used in these two studies was 10% o-xylene, 80% m-xylene and 10% p-xylene (Pryor et al., 1987). Wistar rats (60 males/group) were exposed to 0 or 300 ppm xylene 6 h per day, 5 days per week, for up to 18 weeks, and 50% of the animals had 15-20% ethanol in the drinking water. The xylene used was 19.2% o-xylene, 43.0% m-xylene, 19.5% p-xylene and 18.3% ethylbenzene. It was concluded that concurrent ethanol intake increased hepatic and renal microsomal enzyme activities. Stearosis in the liver was more marked in co-exposed animals than in animals exposed only to ethanol. No treatment-related abnormalities were observed during histopathological examination of animals exposed only to xylene (Elovaara et al., 1980). Exposure to 1000 ppm xylene (not defined) 18 h per day, 7 days per week, for 61 days caused a slight loss of auditory sensitivity in Sprague-Dawley rats. Co-exposure to n-hexane (1000 ppm) caused a persistent loss of auditory sensitivity, which was less than additively enhanced. Xylene inhibited n-hexane-induced impulse velocity reduction in peripheral nerves (Nylén & Hagman, 1994). In a study to investigate the effect on brain lipid composition, Sprague-Dawley rats were exposed to 0 or 320 ppm xylene continuously for 30 or 90 days. The xylene (undefined) produced only limited transient changes (Kyrklund et al., 1987). In another study to investigate the effect on brain with and without co-exposure to ethanol, Wistar rats (20 males/group) were exposed to 0 or 300 ppm xylene 6 h per day, 5 days per week, for up to 18 weeks. In each group were 10 animals also exposed to 15% v/v ethanol in the drinking-water. There was a significant increase in cerebral microsomal superoxide dismutase activity by week 18, but no effect on cerebral protein or RNA levels. Co-exposure to ethanol reduced the effect caused by xylene exposure. The xylene used was 7.5% o-xylene, 85.0% m-xylene and 7.5% p-xylene (Savolainen et al., 1979a,b). In a study of the effect on spinal cord axon membrane, Wistar rats (five animals per group) were exposed to 0 or 300 ppm xylene (undefined) 6 h per day, 5 days per week, for 18 weeks. In exposed animals there was a decrease in the amount of membrane lipid per mg of protein but no change in the cholesterol/lipid phosphorus ratio. Ethanol (15% v/v) in the drinking-water enhanced the decrease and also decreased the cholesterol/lipid phosphorus ratio (Savolainen & Seppäläinen, 1979). In a neurotoxicity study, changes in two astroglial cell marker proteins (S-100 and GFA) and DNA were measured. Mongolian gerbils (four of each sex per group) were exposed to 0, 160 or 320 ppm xylene continously (24 h/day) for 3 months, followed by a 4-month exposure-free period. The xylene used was 18% o-xylene, 70% m-xylene, 12% p-xylene and < 3% ethylbenzene. The exposure to xylene resulted in brain damage which was manifest as an increase in astroglial cells. Effects were seen in particular parts of the brain at both exposure levels but were only significant at 320 ppm (Rosengren et al., 1986). Ageing Long-Evans rats fed 200 ppm o-xylene for up to 6 months showed formation of vacuolar structures in hepatocytes when examined ultrastructurally (Bowers & Cannon, 1982). Groups of 10 male and 10 female Sprague-Dawley rats were exposed to mixed xylenes by gavage (in corn oil) for 90 consecutive days at dose levels of 150, 750 and 1500 mg/kg body weight per day (Condie et al., 1988). The most significant findings were increased relative liver and kidney weights. Histopathology evaluation of liver and kidney tissues revealed an increased incidence of minimal chronic renal disease in females only. Treatment-related hepatic histopathological changes were not detected in either sex. Hyaline droplet formation was observed in male rats in all treated groups. In females, there was an increased incidence of kidney effects, which were thought to represent onset of progressive nephropathy (Condie et al., 1988). Mice (B6C3F1) were given orally 0, 250, 500, 1000 or 2000 mg xylene per kg body weight for 14 days or 0, 125, 250, 500, 1000 or 2000 mg per kg body weight, 5 days per week, for 13 weeks. The xylene used was 9.1% o-xylene, 60.2% m-xylene, 13.6% p-xylene and 17.0% ethylbenzene. Mean body weight gain was reduced in males at > 250 mg/kg body weight. No treatment-related abnormalities were observed at gross necropsy or histopathological examination (NTP, 1986). 7.4 Skin and eye irritation; sensitization Erythema and oedema were induced following a single application (amount not stated) of xylene (not defined) to rabbit or guinea-pig skin. There was a rapid onset and epithelial desquamation, with some evidence of necrosis occurring after several days (Rigdon, 1940; Steele & Wilhelm, 1966). After 24 h of exposure to 0.5 ml xylene (undefined) under semi-occlusive conditions, irritation of rabbit skin was observed. The irritation was graded as moderate by the authors (Hine & Zuidema, 1970). Application of 0.5 ml p-xylene, under a Teflon chamber, to rabbit skin for 4 h produced a response which would be classified as irritant using European Union criteria (Jacobs et al., 1987). In another study, following 10 to 20 applications of xylene (not defined) to open or semi-occluded rabbit skin for up to four weeks, a moderate to marked irritation and moderate necrosis was reported, as was blistering of the skin under the semi-occlusive dressing (Wolf et al., 1956). Application of approximately 0.05 to 0.5 ml of liquid xylenes (individual isomers or undefined composition) to the rabbit eye was reported to cause immediate discomfort and blepharospasm followed by slight conjunctival irritation and very slight, transient corneal necrosis (Wolf et al., 1956). Application of 0.1 ml liquid xylene (not defined) was mildly irritant to rabbit eye. The lesions were not described (Kennah et al., 1989). No skin sensitization studies have been reported. 7.5 Reproductive and developmental toxicity A summary of reproductive and developmental toxicity studies is shown in Table 7. Groups of female rats (CFY) were exposed to 0, 34, 345 or 690 ppm o-xylene 24 h/day from day 7 to day 14 of gestation. The dams were killed on day 21. Some ultrastructural changes in the liver and decreased weight gain during the exposure period were observed in the dams exposed to 345 or 690 ppm. At these concentrations lower fetal body weight was observed, and at the highest dose level delayed skeletal ossification was noted. There was no evidence of malformations. Similar results were obtained when the animals were exposed to m-xylene. With p-xylene there were signs of delayed skeletal ossification at exposure levels showing no maternal toxicity (at 34 and 345 ppm). At 690 ppm, increased postimplantation loss of fetuses and more retarded fetuses were observed (Ungvary et al., 1980). Table 7. Reproductive and developmental effects (inhalation studies) Compound Species Exposure Duration NOEL LOEL Endpoint Reference o, m, p-Xylene rat 0, or 1000 24 h/day; Fused sternebrae, Hudak & Ungvary mg/m3 days 9-14 extra ribs (1978) Xylene rat 0, 10, 50 or 6 h/day; Maternal toxicity not Mirkova et al. (not specified) 500 mg/m3 days 1-21 addressed (1983) Xylene rat 0, 250, 1900 24 h/day; 250 mg/m3 Skeletal retardation Ungvary & Tatrai (not specified) or 3400 days 7-15 (mothers and (1985) mg/m3 offspring) o-xylene rat 0, 150, 1500 24 h/day; 150 mg/m3 150 mg/m3 Decreased fetal weight, Ungvary et al. or 3000 days 7-14 offspring (dams) skeletal retardation (1980) mg/m3 1500 mg/m3 (offspring) m-xylene rat 0, 150, 1500 24 h/day; 1500 mg/m3 3000 mg/m3 Maternal: reduced food Ungvary et al. or 3000 days 7-14 (dams and (dams and consumption, reduced (1980) mg/m3 offspring) offspring) weight gain Offspring: reduced fetal weight p-xylene rat 0, 150, 1500 24 h/day; 150 mg/m3 Reduced mean litter Ungvary et al. or 3000 day 7-15 (dams and size; reduced fetal (1980) mg/m3 offspring) weight; skeletal retardation p-xylene rat 0 or 3000 10th day, Decreased fetal weight Ungvary et al. mg/m3 24 h (1981) Table 7. (Cont'd) Compound Species Exposure Duration NOEL LOEL Endpoint Reference p-xylene rat 0, 3500 or 6 h/day; 7000 7000 mg/m3 Maternal: reduced Rosen et al. 7000 mg/m3 days 7-16 mg/m3 (dams) weight gain (1986) (offspring), 3500 mg/m3 (dams) Xylene rat 0 or 600 24 h/day; Decreased maternal Ungvary (1985) (not defined) mg/m3 day 7-15 weight gain. Delayed fetal development; extra ribs Xylene rat 870 mg/m3 6 h/day; No maternal toxicity; Hass & Jakobsen (not defined) days 4-20 delayed ossification (1993) o, m, p-Xylene rat 2175 mg/m3 6 h/day; Delayed righting reflex; Hass et al. (1995) days 7-20 reduced absolute brain weight; impaired neuromotor ability Xylene mouse 0, 500 or 24 h/day; 500 mg/m3 1000 mg/m3 Skeletal retardation and Ungvary & Tatrai (not specified) 1000 mg/m3 days 6-15 offspring (offspring) increased incidence of (1985) weight-retarded fetuses Xylene rabbit 0, 500 or 24 h/day; 500 mg/m3 Maternal: decreased Ungvary & Tatrai (not specified) 1000 mg/m3 days 7-20 (offspring) weight gain (1985) 1000 mg/m3 Offspring: delayed (dams) skeletal development Rats (CFY) were exposed to 0.58, 437 or 782 ppm 24 h/day on days 7 to 15 of gestation and the dams were killed on day 21. Data concerning maternal toxicity was not given. There was delayed skeletal ossification at all dose levels, while decreased fetal bodyweight, increased postimplantation loss and increased frequency of skeletal variants (extra ribs) were observed at 782 ppm. Mice (CFLP) were exposed to 0 or 115 ppm o-xylene for 4 h, 3 times per day on day 6 to day 15 of gestation, and the dams were killed on day 18. Data concerning maternal toxicity were not reported. There was evidence of delayed weight gain and skeletal ossification in the fetuses of exposed animals. Similar results were obtained with m-xylene and p-xylene (Ungvary & Tatrai, 1985). When rabbits (New Zealand White) were exposed to 0 or 115 ppm o-xylene 24 h/day from day 7 to day 20 of gestation, no maternal toxicity or incidence of delayed development was observed in the exposed group. Similar results were observed with m-xylene, but an increased incidence of post-implantation loss was observed. Exposure to 115 ppm p-xylene gave the same results as with o-xylene, but exposure to 230 ppm p-xylene 24 h/day resulted in no live fetuses (one dam died, three aborted and in four there was total resorption or fetal death in utero) (Ungvary & Tatrai, 1985). In a study to validate a developmental toxicity screen, mice (ICR/SIM) were exposed orally to 0 or 2000 mg m-xylene/kg body weight from day 8 to day 12 of gestation. No effects were seen on mothers or young (Seidenberg et al., 1986). In another study Sprague-Dawley rats were exposed to 0, 800 or 1600 ppm p-xylene, 6 h per day from day 7 to day 16 of gestation. The dams were allowed to deliver their young. In the highest dose group the maternal weight gain was significantly reduced. Exposure to p-xylene had no effects on postnatal viability, offspring growth or function of the nervous system (activity level and acoustic startle response) at any of the doses tested (Rosen et al., 1986). In an attempt to study the effect of xylene on sex steroids during pregnancy, rats (CFY) were exposed to 0 or 681 ppm p-xylene for 24 h on day 10 of gestation or continuously on days 9 and 10 of gestation. The animals were killed on day 11. Data on maternal toxicity were not reported. Sex hormone levels in the uterine and femoral veins were decreased in the exposed group. The authors (Ungvary et al., 1981) suggested that this may play a role in the embryotoxicity. Rats (CFY) were exposed to 0 or 230 ppm xylene for 24 h/day from day 9 to day 14 of gestation, and the dams were killed on day 21. The xylene used was 10% o-xylene, 50% m-xylene, 20% p-xylene and 20% ethylbenzene. No maternal effects were seen in exposed animals. There was an increased incidence of skeletal variants such as extra ribs and fused sternebrae. Three malformations were found (2 agnathia, 1 fissura sterni), but there was no significant increase in the frequency of malformations (Hudak & Ungvary, 1978). In another study rats (CFY) were exposed to 0 or 138 ppm xylene (not defined) 24 h/day from day 7 to day 15 of gestation. The dams were killed on day 21. In the exposed group, decreased maternal weight gain, delayed fetal development and increased incidence of skeletal variants (extra ribs) were observed, but there was no evidence of malformations (Ungvary, 1985). In a report issued by the American Petroleum Institute in 1983, described by Bell et al. (1992), Sprague-Dawley rats were exposed to a xylene mixture of 20.4% o-xylene, 44.2% m-xylene, 20.3% p-xylene and 12.8% ethylbenzene. There were 30 males and 60 females in the control group, while 10 males and 20 females per group were exposed to 60 or 250 ppm xylene and 20 males and 40 females were exposed to 500 ppm xylene. Exposures were 6 h per day, 7 days per week, for a 131-day pre-mating period and a 20-day mating period. Mated females were also exposed during days 1-20 of gestation and days 5-20 of lactation. For males there were no effects on body weight gain, but for females the mean body weight gain was significantly greater than that of controls in the 60 and 250 ppm groups during the mating period. This was not considered indicative of an adverse effect of treatment. Mating indices were significantly lower than control values at 250 ppm (both sexes treated) and at 500 ppm (females treated only), but mating indices were comparable to control values at 500 ppm when both sexes were treated or when males alone were treated. There were no treatment-related effects on mean duration of gestation, mean litter size or pup survival. The mean pup weight in the group where both parents had been exposed to 500 ppm xylene was significantly lower than for controls. In the teratogenicity part of the study there was no evidence of an increased incidence of malformations in exposed groups. The mean fetal weights for the 500 ppm group were lower than the control value, but, the difference was statistically significant for only the female fetuses. Groups of Wistar rats were exposed to 0, 2, 11 or 114 ppm xylene (mixed, not defined) for 6 h per day from day 1 to day 21 of gestation. The maternal toxicity was not reported. The incidence of post-implantation loss and fetal death was significantly increased in the 11 ppm and 114 ppm groups. At the highest dose an increase in some malformations was noted but no incidence was given. The results of the study cannot be evaluated because of insufficient reporting of exposure conditions and results (Mirkova et al., 1983). In an attempt to repeat this study, groups of 36 Wistar rats were exposed to 200 ppm technical xylene 6 h per day on days 4 to 20 of gestation. There were no signs of maternal toxicity. No exposure-related differences were found except for delayed ossification of maxillary bone. The xylene-exposed pups had a slightly higher body weight and impaired performance in a motor ability test, which was most marked in female offspring (Hass & Jakobsen, 1993). In a follow-up study (Hass et al., 1995), Wistar rats were exposed to 500 ppm technical xylene (19% o-xylene, 45% m-xylene, 20% p-xylene and 15% ethylbenzene) for 6 h per day on gestation days 7-20. The dose level was selected so as not to induce maternal toxicity or decrease the viability of offspring. There were 15 exposed litters and 13 control litters. A delay in the development of the air righting reflex, a lower absolute brain weight and impaired performance in behavioural tests for neuromotor abilities, learning and memory were found in the offspring of the exposed rats. Generally, the effects were most marked in the female offspring. The alterations were long-lasting, as they were still apparent in adult rats at the age of 4 months. A composition of 9.1% o-xylene, 60.2% m-xylene, 13.6% p-xylene and 17.0% ethylbenzene was given orally to CD-1 mice. The doses were 0, 520, 1030, 2060, 2580, 3100 or 4130 mg per kg body weight daily from day 6 to day 15 of gestation. All animals in the highest dose group died and so did 50% of the animals in the 3100 mg/kg group. In this group there was a significant increase in the incidence of dams with complete resorptions. There was a significant increase in the incidence of cleft palate at > 2060 mg/kg, as well as decreased mean fetal weight (Marks et al., 1982). In order to study the teratogenic and embryotoxic effects of xylene (60% p-xylene, 22% o-xylene, 18% ethylbenzene; no m-xylene) embryos of Sprague-Dawley rats were explanted on day 9.5 of gestation and cultured in rat serum to which xylene (0.1, 0.5 or 1.0 ml/litre) dissolved in DMSO was added. The embryos were cultured for 48 h. There were no observable teratogenic effects in terms of malformations. However, dose-dependent embryotoxicity in terms of retardation on growth and development was observed (Brow-Woodman et al., 1991). In a similar study (Brown-Woodman et al., 1994) rat embryos were incubated in vitro with up to 2.7 µmol xylene/ml for 40 h. Concentrations of > 1.89 µmol/ml retarded embryo growth and development. The no-observed-effect level (NOEL) was 1.08 µmol/ml. No gross morphological malformations were observed. Combined exposure to toluene, xylene and benzene caused additive embryotoxic effects with no evidence of synergistic action (Brown-Woodman et al., 1994). When Sprague-Dawley rats were exposed to 1000 ppm xylene (not defined) 18 h per day, 7 days per week, for 61 days, testicular atrophy or loss of nerve growth factor-immunoreactive germ cell line was not observed. Xylene also was found to protect from n-hexane-induced testicular atrophy (Nylén et al., 1989). Wistar rats were exposed for 7 days to xylene (isomer not stated) twice a day until disappearance of righting reflex (xylene concentration not given). Anaesthesia was achieved in about 10 min. On day 8 the rats were killed. A decrease in body weight and weights of testes and accessory reproductive organs, as well as reduced acid phosphate activity in the prostate and reduced plasma testosterone levels, was observed in xylene-exposed animals. There was also a decrease in spermatozoan count in the epididymis (Yamada, 1993). 7.6 Mutagenicity and related end-points Technical grade xylene did not produce differential killing in DNA-repair-proficient compared to repair-deficient strains of Bacillus subtilis rec+/- (McCarroll et al., 1981a) or Escherichia coli (McCarroll et al., 1981b). Xylene (type not specified) did not induce SOS activity in Salmonella typhimurium TA1535/pSK 1002 (Nakamura et al., 1987). For E. coli WP2 uvr A p-xylene was not mutagenic in the presence or absence of an exogenous metabolic system from PCB-induced rat liver (Shimizu et al., 1985). None of the isomers nor unspecified xylene was mutagenic to S. typhimurium TA1535, TA1537, TA98, TA100, UTH 8413 or UTH8414 in the presence or absence of a metabolic system from uninduced or Arochlor-induced rat and hamster livers (Lebowitz et al., 1979; Bos et al., 1981; Haworth et al., 1983; Connor et al., 1985; Shimizu et al., 1985; Zeiger et al., 1987). Exposure to technical grade xylene containing 18.3% ethylbenzene caused recessive lethal mutations in Drosophila melanogaster but not exposure to m-xylene, or o-xylene (Donner et al., 1980). The same report stated that exposure to rats for 300 ppm, 6 h per day, 5 days per week for 9, 14 and 18 weeks did not induce chromosomal aberrations in bone-marrow cells (Donner et al., 1980). Xylene (unspecified) did not induce mutations in mouse lymphoma L5178Y TK+/- cells in vitro or chromosomal aberrations in rat bone marrow cells (Lebowitz et al., 1979). Xylene (unspecified) did not induce sister chromatid exchange or chromosomal aberrations in human lymphocytes in vitro. No exogenous metabolic system was used in this study (Gerner-Smidt & Friedrich, 1978). None of the isomers induced micronuclei in the bone marrow of male NMRI mice after two i.p. administrations of 105-650 mg/kg body weight at a 24-h interval, but they did, however, enhance the induction of micronuclei by toluene (Mohtashamipur et al., 1985). When Sprague-Dawley rats were given 440 or 1320 mg o-xylene/kg body weight intraperitoneally, a significant increase in the percentage of abnormal sperm was reported when the animals were housed at 24-30°C (but not at 20-24°C). The authors (Washington et al., 1983) interpreted this as a synergistic effect between o-xylene and temperature. 7.7 Carcinogenicity Group of Sprague-Dawley rats, 40 of each sex, received 500 mg mixed xylenes (composition not specified) per kg body weight in olive oil by stomach tube on 4 to 5 days per week for 104 weeks. Fifty animals of each sex received olive oil only. The animals were maintained until natural death. All animals had died by week 141. At that time thymomas were reported in 1/34 treated males and 0/36 treated females (compared to 0/45 and 0/49, respectively, in controls). Other haemolymphoreticular tumours (not specified) were reported in 4/34 treated males and 3/36 treated females (compared to 3/45 and 1/49, respectively, in controls). The authors (Maltoni et al., 1983; Maltoni et al., 1985) reported an increase in the total number of animals with malignant tumours (type not specified) at 141 weeks, e.g., as 13/38 in treated males and 22/40 in treated females (compared to 11/45 and 10/49, respectively, in control animals). Combining all tumours is, however, not an acceptable basis for analysis particularly in aged animals. No data were provided to allow an analysis on an individual tumour-type basis. In a carcinogenicity study, groups of 50 B6C3F1 mice of each sex were given 0, 500 or 1000 mg xylene/kg body weight in corn oil by stomach tube on 5 days per week for 103 weeks. The xylene used was 9.1% o-xylene, 60.2% m-xylene, 13.6% p-xylene and 17.0% ethylbenzene. The surviving animals were killed within 2 weeks after the last administration. Survival at the termination of the study for males was: 27 controls, 35 low-dose and 36 high-dose; and for females was: 36 controls, 35 low-dose and 31 high-dose. No treatment-related increase in the incidence of any tumour was seen in either sex (NTP, 1986; Huff et al., 1988). The NTP also performed a carcinogenicity study on Fischer-344 rats with the same type of technical xylene. Groups of 50 rats of each sex were given 0, 250 or 500 mg xylene/kg body weight in corn oil by stomach tube 5 days per week for 103 weeks. The surviving animals were killed within 2 weeks following the last administration. At the termination of the experiment, the survival for males was: 36 controls, 25 low-dose and 20 high-dose animals, and for females was: 38 controls, 33 low-dose and 35 high-dose. For the males survival appeared to be dose-related, but many of the early deaths were related to gavage trauma or corn oil-xylene aspiration (3/14, 8/25, 11/30). The incidences of tumours in treated animals of either sex were not significantly higher than in the control group (NTP, 1986; Huff et al., 1988). Two studies have investigated whether exposure to xylenes alters the incidence of experimentally induced skin neoplasia in mice (Pound & Withers, 1963; Pound, 1970). The reporting does not allow any firm conclusions. 7.8 Other effects No effects were observed upon in vitro exposure of human lymphocytes at concentrations up to 2 mM xylene for 72 h. However, at higher concentrations, cell mortality only was significantly increased (Richer et al., 1993). 8. EFFECTS ON HUMANS 8.1 Acute and accidental exposure Acute poisoning and deaths have been reported after overexposure or oral ingestion of substantial amounts of xylene. The exposure level required for loss of consciousness has been estimated to be 10 000 ppm (Morley et al., 1970). At autopsy pulmonary congestion and oedema have been observed after inhalation or oral intake (Morley et al., 1970; Abu Al Ragheb et al., 1986). Among survivors coma, EEG changes, amnesia, mental confusion and ocular nystagmus have been reported. Evidence of gastrointestinal and respiratory symptoms as well as impaired renal and hepatic function have also been observed (Ghislandi & Fabiani, 1957; Recchia et al., 1985; Bakinson & Jones, 1985). After exposure to about 700 ppm (calculated) for up to one hour, headache, nausea, irritation of the eyes, nose and throat, dizziness, vertigo and vomiting have been reported (Klaucke et al., 1982). Recovery seems to be complete in most non-fatal cases although dizziness and vision problems have been observed 24 h after ingestion of xylene (quantity unknown) (Recchia et al., 1985). In a suicidal attempt a 30-year-old man injected 8 ml of xylene intravenously. After 10 min he developed a life-threatening acute pulmonary failure, but survived through medical treatment (Sevcik et al., 1992). 8.2 Controlled human studies A number of volunteer studies have been performed predominantly at the Finnish Institute of Occupational Health. Effects on the sensory motor and information process functions of the central nervous system (CNS) have been investigated. Usually m-xylene has been used, but p-xylene and mixed xylenes have also been studied (Savolainen & Linnavuo, 1979; Savolainen, 1980; Savolainen et al., 1980; Seppäläinen et al., 1981; Savolainen & Riihimäki, 1981; Savolainen et al., 1981; Savolainen et al., 1982a, Savolainen et al., 1982b; Savolainen et al., 1984; Savolainen et al., 1985a, Savolainen et al., 1985b). In these studies no significant effects on vestibular or visual function, reaction times, coordination or peripheral senses were observed during a 4-h exposure to a constant concentration of up to 160 ppm. Slight impairment of vestibular and visual function and reaction time was noted at exposure levels from 200 to 300 ppm. There was adaption to the impairment over five successive daily exposures. In another study (Anshelm Olson et al., 1985), volunteers (n=16) were exposed for 4 h to p-xylene alone (300 mg/m3: 70 ppm) or in combination with toluene (200 mg/m3 toluene plus 100 mg/m3 p-xylene). Heart rate, subjective symptoms, simple reaction time, choice reaction time and short-term memory were unaffected by exposure. In another study nine male volunteers were exposed for 4 h to 200 ppm (TWA) m-xylene. Short-term peak exposures were up to 400 ppm. The effects of xylene on electroencephalography (EEG) were minor and no deleterious effects were noted (Seppäläinen et al., 1991). Healthy male subjects were exposed to technical xylene, containing 40% ethylbenzene, for 2 h with or without a working load of 100 watts. The air concentration was 435 or 1300 mg/m3. During work at the higher exposure level evidence of performance decrement was observed in three of the five performance tests: reaction time addition test (p < 0.05), short-term memory (p < 0.05) and choice reaction time (p < 0.10) (Gamberale et al., 1978). Dizziness was reported by four of six volunteers exposed to 690 ppm p-xylene for 15 min (Carpenter et al., 1975). Nine volunteers were exposed for about 4 h to either a constant or a fluctuating pattern of m-xylene with a time-weighted average exposure concentration of 200 ppm in both cases (Laine et al., 1993). Prolonged simple visual and auditive choice reaction times were observed after exposure to the peaks of 400 ppm m-xylene. Exposure to m-xylene at a constant level of 200 ppm did not affect the ratio of "active" to "quiet" sleep during the following night, but decreased slightly the number of body movements in bed. Studies on coexposure to m-xylene and ethanol (Savolainen, 1980; Seppäläinen et al., 1981; Savolainen & Riihimäki, 1981; Riihimäki et al., 1982a,b; Riihimäki et al., 1982a,b), m-xylene and 1,1,1-trichloroethane (TCE) (Savolainen et al., 1981; Savolainen et al., 1982) or p-xylene and toluene (Anshelm-Olson et al., 1985) have been performed. Exposure to 145-150 ppm xylene and 0.8 g ethanol/kg body weight had an additive disturbing effect on vestibular function. At higher xylene concentrations (275-290 ppm) there was evidence of functional tolerance, and xylene appeared to antagonize the effect of ethanol on vestibular function. In a study where volunteers were exposed to 200 ppm m-xylene, minor effects on vestibular and visual functions and reaction time were reported. Simultaneous exposure to 400 ppm TCE had no further effect. Combined exposure to 60 ppm p-xylene and 30 ppm toluene had no effect on reaction time, short-term memory or heart rate. Ten male volunteers were exposed to 100 ppm xylene (not specified) or 100 ppm toluene or a mixture of 50 ppm of each. Exposure time was 4 h and each person participated in four exposure sessions. Changes in CNS functions were tested by nine psychological tests. Xylene had the most adverse effect on simple reaction time and choice reaction time, while the combined exposure gave weaker effects than xylene alone but stronger than toluene alone (Dudek et al., 1990). A summary of acute effects from inhalation exposure is presented in Table 8. In studies on skin irritation, both hands of subjects were immersed in pure m-xylene (Engström et al., 1977; Lauwerys et al., 1978; Riihimäki, 1979a). A burning sensation was soon noticed and an erythematous reaction was observed in the exposed skin. Of six subjects tested, four reported eye irritation after exposure to 460 or 690 ppm xylene for 15 min. The xylene contained 7.6% o-xylene, 65.0% m-xylene, 7.8% p-xylene and 19.3% ethylbenzene. One subject reported eye irritation at 230 ppm but none at 110 ppm (Carpenter et al., 1975). In another study, no irritation in the eyes, nose or throat was reported after exposure to 98, 196 or 392 ppm mixed xylenes for 30 min (Hastings et al., 1984). In an older study exposure to 200 ppm xylene (undefined) for 3-5 min caused irritation of the eyes, nose and throat (Nelson et al., 1943). The skin sensitization potential was investigated using a non-adjuvant maximization test. The xylene used was not defined. None of 24 subjects tested showed evidence of sensitization (Kligman, 1966). Five adult, healthy, white men were exposed for 7 h per day for 3 days to 40 ppm xylene. This exposure was repeated three times at intervals of 2 weeks. Blood samples were taken before and after each exposure. No significant effects were observed on sister-chromatid exchange frequency, cell cycle time or cell mortality in lymphocytes (Richer et al., 1993). 8.3 Occupational exposure In workers exposed to xylene or solvent mixtures containing large amounts of xylene, subjective symptoms have been reported (Joyner & Leak Pegues, 1961; Glass, 1961; Hipolito, 1980; Kilburn et al., 1983; Kilburn et al., 1985). Depression, fatigue, headache, anxiety, feeling of drunkenness and sleep disorders were the most common symptoms reported, but exposure levels and duration were often missing in these reports. Workers occupationally exposed to solvent mixtures including xylene have been reported to have neurophysiological and psychological disorders (Lindström, 1973; Seppäläinen et al., 1978; Elofsson et al., 1980; Husman, 1980; Husman & Karli, 1980; Arlien-Soborg et al., 1981; Lindström et al., 1982; Valciukas et al., 1985; Maizlish et al., 1987; Van Vliet et al., 1987; Ruijten et al., 1994). In these studies there was no exposure to xylene alone. Xylene was not the main solvent in the mixture. No conclusions concerning effects of xylenes as such can be drawn from these studies. Table 8. Single inhalation exposure to xylene in humans Exposure Time Effect Reference concentration (mg/m3) 3 000 1 h Dizziness, irritation Klaucke et al. (1982) 3 000 15 min Dizziness Carpenter et al. (1975) 1300a 2 h Performance decrement Gamberale et al. (1978) 900b 4 h Prolonged reaction times Laine et al. (1993) 900 4 h Impairment of vestibular and visual Savolainen et al. function and prolonged reaction time (1979, 1981, 1982, 1985) 900 4 h Minor effect on EEG Seppäläinen et al. (1991) 600 4 h No effect on reaction time Savolainen et al. (1980, 1981) 450 4 h Prolonged reaction time Dudek et al. (1990) 300 4 h No effects in psychophysiological test Anshelm - Olson et al. (1985) a during exercise b peak values of 1800 mg/m3 Liver effects have been reported in some studies on workers occupationally exposed to solvents containing xylene (Dössing et al., 1981; Edling, 1982; Sotaniemi et al., 1982; Dössing et al., 1983; Fischbein et al., 1983, Lundberg et al., 1994) but these were not confirmed in other studies (Craveri et al., 1982; Kurppa & Husman, 1982; Lundberg & Håkansson, 1985). Recent findings seem to support the concept that the hepatotoxicity of xylene is low (Riihimåki & Hännien, 1987). Some case studies and epidemiological studies have addressed a possible association between occupational exposure to hydrocarbons (including xylene) and proliferative glomerulonephritis (Beirne & Brennan, 1972; Zimmerman et al., 1975; Lagrue, 1976). Exposures have, however, been so diverse that the role of xylene is impossible to assess. A Swedish group of researchers reported a higher concentration of albumin, erythrocytes and leukocytes in the urine of workers exposed predominantly to xylenes and toluene than among controls (Askergren et al., 1981a,b,c; Askergren, 1981). Franchini et al. (1983) found that painters exposed to toluene and xylenes at relatively low concentrations had a higher excretion of kidney tubular enzymes in their urine than the controls. They suggested that the mixed solvents may exert a slight adverse effect on the kidney tubules. One case of contact urticaria due to occupational exposure to airborne xylene has been reported. The level of xylene in air exceeded 100 ppm. Direct skin contact with the solvent appeared to have been negligible. The contact urticaria seemed likely to be an immunological type (Palmer & Rycroft, 1993). Thirty-five male spray varnishers were exposed to 0.5-3.4 ppm o-xylene, 3.2-11.7 ppm m-xylene, 0.9-4.3 ppm p-xylene, 1.4-7.5 ppm ethylbenzene, < 1.5 ppm toluene, < 1.2 ppm n-butanol, < 35.5 ppm 1,1,1-trichloroethane and several C9 aromatics. In addition, some of the lacquers contained lead pigments. The mean peripheral erythrocyte counts and haemoglobin levels were decreased in the exposed men compared to controls. Whether these effects were due to xylene or the solvent mixture is uncertain (Angerer & Wulf, 1985). The health effects on 175 factory workers in China exposed to xylene vapour with a mixture of three isomers at a concentration of up to 175 ppm (with time-weighted average geometric mean concentration of 14 ppm and arithmetic mean of 21 ppm) were studied. There was an increased prevalence of subjective symptoms in the exposed workers; these were apparently related to effects on the central nervous system and to local effects on the eye, nose and throat (Uchida et al., 1993). In workers exposed to a maximum concentration of 103 ppm xylene (geometric mean 4 ppm) and 203 ppm toluene (geometric mean 3 ppm), the prevalence of some subjective CNS-related symptoms was higher than in the controls (Chen et al., 1994). No effects on haematology or serum biochemistry with respect to liver and kidney functions were observed in these two studies. Sister-chromatid exchanges (SCE) in peripheral lymphocyte cultures have been studied in two groups of 23 workers who had been exposed for between 4 months and 23 years to mixed xylenes (including ethylbenzene). The exposure levels for the two groups were 11 and 13 ppm, respectively. No differences in SCE frequency was seen (Pap & Varga., 1987). A few other reports have described increased incidence of chromosomal aberrations or effects on sister-chromatid exchange frequencies (Funes-Cravioto et al., 1977; Haglund et al., 1980). In both these studies the exposure to xylene (not defined) was accompanied by exposure to other solvents, including benzene. No data on carcinogenic effects resulting from exposure to xylenes have been found in the literature. In an investigation into the effect on reproduction, the outcome of pregnancy was studied among university laboratory employees exposed to xylene (not defined) during the first trimester of pregnancy. Exposure levels were not given. There was no difference in miscarriage rate when compared to controls not exposed to solvents (Axelsson et al., 1984). A similar case control study on associations between laboratory work and pregnancy outcome revealed that use of xylene for 3 or more days a week during the first trimester was significantly associated with an elevated risk of spontaneous abortion. The authors pointed out, however, that laboratory workers were often exposed to several solvents and chemicals simultaneously; only two cases and two controls were exposed to xylene alone (Taskinen et al., 1994). About half of the women exposed to xylene worked in pathology/histology laboratories where there was concomitant exposure to formaldehyde vapour. Formaldehyde (formalin) also appeared to be a significant risk factor for spontaneous abortion. Exposure to xylene was also noted to be associated with an increase in birth weight (Taskinen et al., 1994). 9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD 9.1 Laboratory experiments 9.1.1 Microorganisms Bringmann & Kuhn (1977, 1978) exposed the bacterium Pseudomonas putida for 16 h and the blue-green alga Microcystis aeroginosa for 8 days to xylene. They found a reduction in cell multiplication at concentrations of >200 mg/litre. Walton et al. (1989) studied the effect of p-xylene on the microbial respiration of two soil types, a silt loam (1.49% organic carbon) and a sandy loam (0.66% organic carbon). The chemical was applied at a rate of 1000 µg/g (dry weight). Microbial respiration, as measured by CO2 efflux, of the silt loam was unaffected. In the sandy loam, the CO2 efflux initially decreased and then increased, but returned to control levels within the 6-day exposure period. All three isomers have been shown to inhibit the respiration of sewage sludge utilizing biogenic substrates. Two screening tests were used, RIKA (respiration inhibition kinetic analysis) and OECD 209. The concentration of each compound used was at the limit of the solubility in the medium (approx. 175-198 mg/litre). Inhibitions in the respiration rate of 100% were found for all three isomers in the RIKA screening test, and inhibitions of 22% ( o-xylene) and 43% ( p-xylene) were measured in the OECD 209 screening test. m-Xylene was only tested at a concentration of 0.3 mg/litre in the OECD 209 screening test, which resulted in 5% inhibition (Volskay & Grady, 1990). The toxicity of xylene to three species of environmental bacteria has been determined using assays in sealed serum bottles to prevent loss of chemical by volatilization. Activity of the bacteria was measured by either gas production over 48 h (methanogens), oxygen consumption over 15 h (aerobic heterotrophs) or ammonia use over 24 h (Nitrosomonas). IC50 values (the concentration required to inhibit the bacterial activity by 50%, as compared with controls) for xylene were 250 mg/litre for methanogens, 1100 mg/litre for aerobic heterotrophs and 100 mg/litre for Nitrosomonas (Blum & Speece, 1991). 9.1.2 Aquatic organisms Xylene isomers are highly volatile and disappear rapidly from solution. For example, Mackay & Wolkoff (1973) found that in agitated water, 1m deep and with a 1m2 surface for evaporation, the half-life for o-xylene was 39 min. When Benville & Korn (1977) monitored the loss of xylene from solution during LC50 tests, average percentage losses for the four time intervals studied (24, 48, 72 and 96 h) were 29, 61, 84 and > 99% respectively. These losses mean that the exposure can be difficult to determine. For example, many of the 24-h and 96-h LC50 values are the same or similar, suggesting that most of the xylene had been lost during the test. Galassi et al. (1988), using a closed static system, found mean measured concentrations of xylene and other aromatics to fluctuate by only 10% during the test period of up to 96 h. Care must therefore be taken when interpreting data from open static tests over longer periods than 24 h, especially those based on nominal concentrations. Overall it can be stated that xylene has moderate to low acute toxicity for aquatic organisms. 184.108.40.206 Algae Bringmann & Kühn (1977) exposed the green alga Scenedesmus quadricauda for 8 days to xylene. They found reduction in cell multiplication at concentrations of > 200 mg/litre. Brooks et al. (1977) studied the effect of xylene on photosynthesis in a mixed ocean culture of phytoplankton. They found that exposure to a concentration of 3 mg/litre xylene for 8 h caused a 50% reduction in photosynthesis. Galassi et al. (1988) calculated the 72-h EC50 for growth inhibition in the alga Selenastrum capricornutum to be 4.7, 4.9 and 3.2 mg/litre for the ortho, meta and para isomers, respectively. Similar results were obtained by Herman et al. (1990). Using the same species of algae, they obtained 8 day EC50 values for growth inhibition of 4.2, 3.9 and 4.4 mg/litre for the ortho, meta and para isomers, respectively. Sheedy et al. (1991) reported a 14-day EC50 for growth inhibition of Selenastrum capricornutum of 72 mg/litre for xylene (composition not stated). Hutchinson et al. (1980) exposed the algae Chlamydomonas angulosa and Chlorella vulgaris to p-xylene for 3 h. EC50 values for inhibition of photosynthesis (measured using 14CO2 uptake) were 45.7 and 105.1 mg/litre for the two species, respectively. Kauss et al. (1973) exposed the green alga Chlorella vulgaris to o-xylene and studied growth over a 10-day period in an open system. At nominal concentrations of between 25 and 100 mg/litre, a short-term toxic effect was observed. However, the algal culture recovered within 2 days. The authors pointed out that recovery was probably due to volatilization of the chemicals. A near-saturation concentration of 171 mg o-xylene/litre proved to be acutely toxic and the alga did not recover. Concentrations of 25 and 50 mg o-xylene/litre progressively increased the lag period between initial inoculation and growth. An o-xylene concentration of 100 mg/litre delayed the onset of growth for 4 days and a near-saturation concentration of 171 mg/litre caused complete inhibition of growth during the 10-day exposure period (Kauss & Hutchinson, 1975). Dunstan et al. (1975) exposed marine microalgae, the diatom Skeletonema costatum, the dinoflagellate Amphidinium carterae, the coccolithophorid Cricosphaera and the green flagellate Dunaliella tertiolecta, to xylene for 3 days. A xylene concentration of 10 mg/litre inhibited the growth of all species. Inhibition was most marked in A carterae and S. costatum. 220.127.116.11 Higher plants Frank et al. (1961) exposed the angiosperm pondweeds Elodea canadensis, Potamogeton nodosus and P. pectinatus to xylene (plus 2% emulsifying agent) under static, open conditions for a period of four weeks. A concentration of 100 mg/litre was found to be toxic (8.6 on an injury scale of 0 to 10) but 5 mg/litre was not. Both 300 and 600 mg/litre were similarly toxic after 30-min exposures in flowing water. 18.104.22.168 Protozoa Bringmann et al. (1980) exposed the flagellate protozoan Chilomonas paramaecium to xylene for 48 h and found an initial reduction (5%) in cell multiplication at concentrations of > 80 mg/litre. Rogerson et al. (1983) exposed the ciliate protozoan Colpidium colpoda to xylene in an "open" system consisting of a covered watchglass with an air space. Toxicity thresholds were 1.75 mg/litre (16.5 mmol/m3) for o-xylene and 162 mg/litre (1530 mmol/m3) for m-xylene; no threshold was calculated for p-xylene. The same authors exposed the protozoan Tetrahymena ellioti to xylene isomers in a closed system with no air space. Toxicity thresholds for o-, p- and m-xylene were 18.5, 16.9 and 55.7 mg/litre (174, 159 and 525 mmol/m3), respectively. 22.214.171.124 Invertebrates The LC50 values of xylene to aquatic invertebrates are summarized in Table 9. Le Gore (1974) exposed Pacific oyster larvae (Crassostrea gigas) to o- and p-xylene for 48 h. LC50 values were 0.17 and 0.58 mg/litre for the two isomers, respectively, suggesting that this organism is one of the more sensitive invertebrates to xylene exposure. However, no experimental details were given for these toxicity tests, which makes them difficult to interpret. Table 9. LC50 values of xylenes to aquatic invertebrates Organisms Size/ Static/ Open/ Temp. Hardness Isomer Duration Concentration Reference life-stage flowa closeda (°C) (mg/litre)c (mg/litre)d Estuarine and marine invertebrates Pacific oyster larvae ortho 48 h 0.17 Le Gore (1974) (Crassostrea larvae para 48 h 0.58 Le Gore (1974) gigas) Grass shrimp static c 21 15s 96 h 7.4 Neff et al. (1976) (Palaemonetes static c 21 15s 24 h 14.0 Tatem et al. (1978) pugio) 96 h 7.4 Tatem et al. (1978) Bay shrimp adult static o 16 25s ortho 24 h 4.7 n Benville & Korn (1977) (Crago adult static o 16 25s ortho 96 h 1.1 n Benville & Korn (1977) franciscorum) adult static o 16 25s meta 24 h 4.1 n Benville & Korn (1977) adult static o 16 25s meta 96 h 3.2 n Benville & Korn (1977) adult static o 16 25s para 24 h 1.7 n Benville & Korn (1977) adult static o 16 25s para 96 h 1.7 n Benville & Korn (1977) Dungeness crab zoeae static+ 13 30s ortho 48 h 38 n Caldwell et al. (1977) (Cancer zoeae static+ 13 30s ortho 96 h 6 n Caldwell et al. (1977) magister) zoeae static+ 13 30s meta 48 h 33 n Caldwell et al. (1977) zoeae static+ 13 30s meta 96 h 12 n Caldwell et al. (1977) Table 9. (Cont'd) Organisms Size/ Static/ Open/ Temp. Hardness Isomer Duration Concentration Reference life-stage flowa closeda (°C) (mg/litre)c (mg/litre)d Freshwater invertebrates Water flea static o 24 h >100<1000 n Dowden & Bennett (1965) (Daphnia magna) static 24 h 165 n Brigmann & Kühn (1982) static c ortho 24 h 1 m Galassi et al. (1988) static c meta 24 h 4.7 m Galassi et al. (1988) static c para 24 h 3.6 m Galassi et al. (1988) 4-6 days static c ortho 48 h 3.2 n Bobra et al. (1983) 4-6 days static c meta 48 h 9.6 n Bobra et al. (1983) 4-6 days static c para 48 h 8.5 n Bobra et al. (1983) < 24 h flow o 17 44.7 ortho 48 h 3.82 m Holcombe et al. (1987) Mosquito larvae static o 24-26 24 h 13.9 Berry & Brammer (1977) (Aedes aegypti) Snail (Aplexa adult flow o 17 44.7 ortho 96 h >22.4 m Holcombe et al. (1987) hypnorum) a static = static conditions (water unchanged for duration of test); b o = open; c = closed static+ = semi-static conditions (water renewed at 24 hour intervals); c s = salinity (%) flow = flow-through conditions (xylene concentration in water continuously maintained) d m = measured; n = nominal Berry & Brammer (1977) exposed mosquito larvae (Aedes aegypti) to xylene under static, open conditions at 25°C. Larvae were exposed for 24 h, since no detectable levels of any water-soluble component remained after that period. A non-lethal concentration of 7.92 mg/xylene litre was reported. However, the authors found that bioassays using different volumes of solution and different sized containers demonstrated the significant effect that surface area, volume and depth can have on the results of experiments with volatile hydrocarbons such as xylenes. Falk-Petersen et al. (1985) exposed sea urchin (Strongy locentrotus droebachiensis) eggs to o-xylene from fertilization and monitored deaths, pathology, inhibition of cleavage and differentiation, and pigment effects. Eggs were maintained in test beakers covered with aluminium foil. They calculated a 96-h EC50, based on all these parameters, of 4.1 mg/litre. Freshwater mussels (Dreissena polymorpha) were exposed to various concentrations of xylene, and the behaviour of the mussels in terms of shell valve movements was monitored. At the start of the experiment, all valves were gaping continuously. After a certain period of toxicant addition, a gradual increase in valve closure period was observed. Finally, total closure of shell valves was observed. Effects were first seen at a xylene concentration of 11.9-19.4 mg/litre (nominal) (Slooff et al., 1983). 126.96.36.199 Vertebrates The LC50 values of xylene to fish are summarized in Table 10. Morrow et al. (1975) found that 100 mg xylene/litre killed 100% of young coho salmon (Oncorhynchus kisutch) within 24 h under static, closed conditions. Concentrations of 1 and 10 mg/litre did not cause significant mortality within the 96-h exposure period. Toxicity included rapid, violent and erratic swimming, "coughing", loss of equilibrium and death. Rainbow trout (Oncorhynchus mykiss) significantly avoided xylene (plus 2% emulsifying agent) at a nominal concentration of 0.1 mg/litre during a 1-h test. Fish exposed to 0.001 mg/litre did not show significant avoidance and those exposed to 0.01 mg/litre were significantly attracted to the xylene (Folmar, 1976). Maynard & Weber (1981) found that juvenile coho salmon were able to significantly avoid o-xylene concentrations of > 0.2 mg/litre water. Slooff (1979) exposed rainbow trout Oncorhynchus mykiss to various concentrations of xylene in a flow-through, closed system and monitored any effects of the chemical on their breathing. The lowest concentration at which a toxic condition developed within 24 h after toxicant administration was 2 mg/litre. Table 10. LC50 values of xylenes to fish Organisms Size/ Static Open/ Temp. Hardness Isomer Duration Concentration Reference lifestage /flowa closedb °C (mg/litre)c (mg/litre)d Freshwater fish Fathead minnow 1-2 g static o 25 20 24 h 28.8 n Pickering & Henderson (Pimephales 1-2 g static o 25 20 48 h 27.7 n (1966) promelas) 1-2 g static o 25 20 96 h 26.7 n 1-2 g static o 25 360 24 h & 96 h 28.7 n 0.3 g flow o 17 44.7 ortho 96 h 16.1 m Holcombe et al. (1987) Bluegill 1-2 g static o 25 20 24 h 24 n Pickering & Henderson (Lepomis 1-2 g static o 25 20 48 h 24 n (1966) macrochirus) 1-2 g static o 25 20 96 h 20.9 n 1.1 g flow o 17 44.7 ortho 96 h 16.1 m Holcombe et al. (1987) Goldfish 1-2 g static o 25 20 24 h & 96 h 36.8 n Pickering & Henderson (Carassius (1966) auratus) 20-80 g flow 17-19 80 24 h 30.6 m Weber et al. (1975) 20-80 g flow 17-19 80 96 h 16.9 m 3.3 g static o 19-21 ortho 24 h 13 m Bridie et al. (1979) 3.3 g static o 19-21 meta 24 h 16 m 3.3 g static o 19-21 para 24 h 18 m 2.5 g flow o 17 44.7 ortho 96 h 16.1 m Holcombe et al. (1987) Table 10. (Cont'd) Organisms Size/ Static Open/ Temp. Hardness Isomer Duration Concentration Reference lifestage /flowa closedb °C (mg/litre)c (mg/litre)d Guppy 0.1-0.2 g static o 25 20 24 h & 96 h 34.7 n Pickering & Henderson (Poecilia (1966) reticulata) static meta 14 days 305 Könemann (1981) static ortho 7 days 291 static para 7 days 285 static c 20-22 ortho 96 h 12 m Galassi et al. (1988) static c 20-22 meta 96 h 12.9 m static c 20-22 para 96 h 8.8 m Rainbow trout static c 11-13 ortho 96 h 7.6 m Galassi et al. (1988) (Oncorhynchus static c 11-13 meta 96 h 8.4 m mykiss) static c 11-13 para 96 h 2.6 m flow o 9-13 89.5 96 h 10e Folmar (1976) 13.1 g flow o 17 44.7 ortho 96 h 8.05 m Holcombe et al. (1987) 0.9 g flow o 12 40-48 technical 24 h & 96 h 13.5 Walsh et al. (1977) Zebra fish flow c 48 h 20 Sloff (1979) (Brachydanio rerio) Table 10. (Cont'd) Organisms Size/ Static Open/ Temp. Hardness Isomer Duration Concentration Reference lifestage /flowa closedb °C (mg/litre)c (mg/litre)d Golden orfe 1.2-1.8 g static 48 h 86f Juhnke & Lüdemann (Leuciscus 1.2-1.8 g static 48 h 308f (1978) idus melanotus) White sucker 2.4 g flow o 17 44.7 ortho 96 h 16.1 m Holcombe et al. (1987) (Catostomus commersoni) Marine fish Coho salmon young static c 8 30s 24 h > 10 < 100 Morrow et al. (1975) (Oncorhynchus kisutch) Striped bass 6 g static o 16 25s ortho 24 h & 96 h 9.7 n Benville & Korn (1977) (Morone 6 g static o 16 25s meta 24 h & 96 h 7.9 n saxatilis) 6 g static o 16 25s para 24 h & 96 h 1.7 n a static = static conditions (water unchanged for duration of test); flow = flow-through conditions (xylene concentration in water continuously maintained) b o = open; c = closed c s = salinity (°/oo) d m = measured; n = nominal e included 2% emulsifying agent f results from two different laboratories When Walsh et al. (1977) exposed rainbow trout (average weight 165 ± 86 g) to xylene concentrations of 0.31, 0.65 and 1.1 mg/litre in artificial streams for 56 days, no adverse effects on the fish were noted at any concentration. Using the same artificial streams, all rainbow trout exposed to xylene concentrations of 14.2 or 22.5 mg/litre for 2 h died. Fish exposed to xylene concentrations of 3.2 and 6.2 mg/litre for 2 h showed symptoms similar to anaesthesia. Kjorsvic et al. (1982) exposed cod eggs ( Gadus morhus L.) to xylene isomers in covered glass dishes and monitored the effects both during fertilization and during early cleavage of fertilised eggs. Both m-xylene and p-xylene induced significant decreases in the fertilization rate at concentrations above 10 mg/litre. o-Xylene had no significant effect on the fertilization rate at concentrations of 16-35 mg/litre. Fertilized eggs were exposed to xylene for 3 or 6 h before first cleavage. No significant difference was observed between the individual xylene isomers or between the two exposure periods. Effects on the early cleavage pattern were significant for xylene concentrations between 2 and 7 mg/litre. The effects seen included inhibition of formation of the cleavage furrow. Small cells or a total absence of cleavage occurred on exposure to all isomers at concentrations of 16-35 mg/litre, while incomplete or uneven cleavage was found at exposures of 8-15 mg/litre. Black et al. (1982) exposed embryo-larval stages of the leopard frog Rana pipiens and rainbow trout (Oncorhynchus mykiss) to m-xylene from 30 min after fertilization to 4 days after hatching in a closed, flow-through system (hatching times were 5 days for the frog and 23 days for the trout). LC50 values of 3.53 and 3.77 mg/litre were calculated for the two species, respectively. 9.1.3 Terrestrial organisms Hill & Camardese (1986) exposed Japanese quail (Coturnix coturnix japonica) to xylene in 5-day dietary toxicity tests. The LC50 was found to be greater than 20 000 mg/kg diet. No overt signs of toxicity occurred at 5000 mg/kg. No studies on terrestrial plants, terrestrial invertebrates or field effects of xylenes have been reported. 10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT 10.1 Evaluation of human health risks 10.1.1 Exposures In the general environment humans are exposed to xylenes mainly by inhalation. Absorption through the skin may also occur in the working environment. The retention in the lungs is about 60% of the inhaled dose. Xylene is efficiently metabolized. More than 90% is biotransformed to methylhippuric acid, which is excreted in urine. Xylene does not accumulate significantly in the human body. Typically, mean background levels of all three xylene isomers in ambient air are around 1 µg/m3 with levels of 3 µg/m3 in suburban areas. Higher levels have been measured in urban and industrialized areas with mean concentrations ranging up to 500 µg/m3; however, concentrations are generally below 100 µg/m3. The estimated daily exposure of the general population through inhalation is 70 µg in rural areas and less than 2000 µg in urban areas. The concentration in drinking-water ranges from not detectable to 12 µg/litre. Data on the levels in food are too limited to estimate daily oral exposure. 10.1.2 Effects Based on experimental human studies, xylene may have an acute impairing effect on the sensory-motor and information-processing functions of the central nervous system (CNS). Exposure to 435-870 mg/m3 (100-200 ppm) of xylene over 4 h caused slight impairments in reaction time performance and vestibular functions. There was adaptation at 200 ppm m-xylene to the impairment over five successive days. The LOAEL of xylene for acute CNS effects, based on one study, is 470 mg/m3 (108 ppm). It should be noted, however, that other identical studies found significant effects only at concentrations of 870 mg/m3 (200 ppm) or more. According to a study by a different research group, exposure to 304 mg/m3 (70 ppm) p- xylene for 4 h did not cause impairment of corresponding psycho- physiological functions; 304 mg/m3 (70 ppm) xylene can therefore be regarded as the NOAEL for acute CNS effects. Xylene vapour becomes irritating at relatively high levels. Among six volunteer subjects, four reported eye irritation after exposure to 2000 or 3000 mg/m3 (460 or 690 ppm) xylene for 15 min while one subject reported eye irritation at 1000 mg/m3 (230 ppm) and none at 478 mg/m3 (110 ppm). According to another study, no irritation of the eyes, nose or throat was reported after exposure to 423, 852 or 1705 mg/m3 (98, 196 or 392 ppm) mixed xylenes for 30 min. These human findings are consistent with mouse studies showing that strong irritancy (respiratory rate decrease by 50%) occurs at about 5960 mg/m3 (1370 ppm) xylene. The odour threshold for xylene is about 1 ppm. Subjective symptoms have been reported among workers exposed to solvent mixtures containing large amounts of xylene. Long-term exposure to xylene is suspected to affect the nervous system adversely because chronic toxic encephalopathy and milder functional disturbances of the brain have sometimes been found among exposed painters and other workers. Likewise, slight changes in kidney tubular function may occur. The specific role of xylene in these effects cannot, however, be ascertained. When human data are sparse, especially data from chronic studies, animal data are used as a substitute. An assessment of the risk to human health of exposure to xylene must rely on animal studies. Apparently irreversible effects on the CNS were found 4 months after a 3-month inhalation exposure (24 h per day) of Mongolian gerbils to xylene at concentrations of 696 or 1392 mg/m3 (160 or 320 ppm). At the lower level the effects were not statistically significant in any individual part of the brain but the changes were all of the same nature. The study disclosed an increased concentration of astroglial proteins in most brain regions studied, which may indicate that glial proliferation is characteristic to various neurodegenerative and neurotoxic states. In the light of similar findings in animals exposed to other solvents (e.g., trichloroethylene, ethanol and tetrachloroethylene), the results are estimated to be an important piece of evidence for potential xylene-induced neurotoxicity at > 696 mg/m3 (160 ppm) (the LOAEL). Functional changes, similar to acute effects on nervous functions, were described after exposure to 435 mg/m3 (100 ppm), but they cannot be discriminated from the acute effects of the last exposure. The exposure level is consistent with the levels giving acute effects in humans, as stated above. No adequate studies of reproduction and development toxicity in humans exposed to xylene alone have been published. Placental transfer of xylene has been shown in humans and in experimental animals. Teratogenicity studies in pregnant animals exposed to technical xylene or xylene isomers during organogenesis indicate that xylene may cause reduced fetal weight and delayed ossification, but not malformations, at dose levels causing no or only slight maternal toxicity. LOAEL values of 500-2175 mg/m3 (115-500 ppm) have been reported, depending on the length of the daily exposure periods (6-24 h/day). Signs of delayed ossification in the absence of lower fetal body weight have been reported at lower dose levels. However, these findings cannot be properly evaluated owing to incomplete description of the criteria for assessing ossification. A NOAEL for delayed fetal development cannot therefore be established. In a study of postnatal development in rat offspring prenatally exposed to 870 or 2175 mg/m3 (200 or 500 ppm) technical xylene, behavioural impairments indicating effects on the development of the central nervous system were detected. There was no maternal toxicity, and the effects at 2175 mg/m3 (500 ppm) were long-lasting as they were apparent in adult offspring. As 870 mg/m3 (200 ppm) was the lowest dose level investigated for this effect a NOAEL could not be established. In several short-term and long-term animal studies, effects on the activities of various metabolic enzymes in different organs have been observed. Exposure to 217 mg/m3 (50 ppm) m-xylene 6 h/day for 5 days induced renal cytochrome P-450. At 1305 mg/m3 (300 ppm) xylene (6 h/day for 14 days) an increase in hepatic and renal enzyme activities was observed. At > 1740 mg/m3 (400 ppm) increases in hepatic and renal metabolic enzyme levels, as well as increased relative liver and kidney weights, have been reported. At the same exposure levels the pulmonary P-450 content and pulmonary enzyme activities were decreased. When rats were orally given 150 mg xylene/kg body weight per day for 90 days, increased relative liver weights were seen. These changes in metabolic enzyme activities and increased relative liver weight could be taken as an indication of metabolic adaptation rather than toxicity. When rats were exposed to 3480 mg/m3 (800 ppm) xylene, 14 h/day, 7 day/week for 6 weeks, an increased auditory response threshold was reported. Thus, 3480 mg/m3 (800 ppm) is the LOAEL for ototoxicity. For this effect no NOAEL could be established as 3480 mg/m3 (800 ppm) was the lowest dose level used. Xylene appears not to be a mutagen or a carcinogen. 10.1.3 Guidance value The definition and aim of guidance values for the general population have been described by IPCS (1994). Although some differences in action between the three isomers exist, there is no clear evidence that they (or mixture of them) have totally different effects. There have been no long-term controlled human studies or epidemiological studies from which a guidance value may be calculated. Epidemiological data from the occupational setting do not allow an estimation of xylene-specific chronic nervous system effects, neither can the neuropsychological impairment seen among solvent-exposed workers be attributed to any specific level of xylene in air. On the basis of human volunteer studies (Anshelm Olson, 1985), one may conclude that the NOAEL for acute CNS effects in humans is about 304 mg/m3 (70 ppm) for a 4-h exposure. The use of an uncertainty factor of 10 for intraspecies variability (the study subjects were healthy male research workers) and an additional factor of 6 (4-h exposure versus 24-h general population exposure) leads to a guidance value of 4.8 mg/m3 (1.1 ppm). It should be noted, however, that the acute CNS effect observed probably has no predictive value for chronic CNS toxicity by xylene. The guidance value of 4.8 mg/m3 (1.1 ppm) is close to the odour threshold of xylene. It should be noted that a subset of the human population may be sensitive enough to experience the odour as annoying. The Task Group considered that there was no need to add another uncertainty factor for the lack of data from chronic exposure. On the basis of animal studies on developmental toxicity, one may conclude that the LOAEL for reduced fetal body weight is 500 mg/m3 (115 ppm) (Ungvary & Tatrai, 1985) and that for developmental neurotoxicity is 870 mg/m3 (200 ppm) (Hass & Jakobsen, 1993). Developmental neurotoxicity is a serious effect that may be long-lasting and is therefore considered the critical effect. An uncertainty factor of 10 for use of a LOAEL rather than a NOAEL seems justified based on the evidence of lower fetal body weight at 500 mg/m3 (115 ppm) and limited evidence of delayed ossification at even lower exposure levels. The use of additional factors of 10 for interspecies variation and 10 for inter-individual variation leads to a guidance value of 0.87 mg/m3 (0.2 ppm). Using the hearing loss (Pryor et al., 1987) detected in animals after exposure to 3480 mg/m3 (800 ppm) xylene for 6 weeks as a starting point, an uncertainty factor of 10 for use of a LOAEL rather than a NOAEL, a factor of 10 for interspecies variation and an additional factor of 10 for inter-individual variation results in a guidance value of 3.48 mg/m3 (0.8 ppm). A neurotoxicity study in animals exposed continuously for 3 months to 696 or 1392 mg/m3 (160 or 320 ppm) xylene (Rosengren et al., 1986) provided suggestive biochemical evidence of an apparently irreversible adverse effect on the nerve cells of the brain even at the lower level. Although there may be uncertainty concerning the biological significance and interpretation of the findings, the Task Group considered them potentially important and recommended further confirmatory studies. With respect to animal-human extrapolation and relatively short exposure, the estimate of the critical level for life-long exposure in humans is 1.6 ppm. A guidance value of 0.87 mg/m3 (0.2 ppm) covers another uncertainty factor of approximate 10 in this respect. Based on the above considerations, the Task Group recommended 0.87 mg/m3 (0.2 ppm) as a guidance value for the general population. This value was derived from the LOAEL reported for developmental neurotoxic effects in laboratory animals. 10.2 Evaluation of effects on the environment 10.2.1 Exposure The majority of xylene released into the environment will enter the atmosphere directly. In the atmosphere the xylene isomers are readily degraded. Volatilization to the atmosphere from water is rapid for all three isomers. Although the meta and para isomers are readily biodegraded, in soil and water the ortho isomer is more persistent. Bioaccumulation of xylene isomers by aquatic organisms is low. Typically, mean background levels of all three xylene isomers in ambient air are around 1 µg/m3. Mean background concentrations of xylenes in surface waters are generally below 0.1 µg/litre. However, higher values have been measured in industrial areas. In areas associated with the oil industry even higher levels have been reported but only associated with discharge pipes. Similar background levels have been reported for groundwater, although localized pollution can lead to higher levels. 10.2.2 Effects The xylene isomers are of moderate to low toxicity to aquatic organisms. The variation between each individual isomer with respect to aquatic toxicity is generally small. The lowest LC50 value, based on measured concentrations, is for a 24-h exposure of Daphnia magna to 1 mg o-xylene/litre. There is limited information regarding chronic exposure of aquatic organisms to xylenes and none of the observed effect levels were lower than those summarized under the acute studies. The acute toxicity of xylene to birds is low. 10.2.3 Risk evaluation Xylenes are rapidly degraded in the environment. However, the photooxidation reactions of the xylene isomers in the atmosphere may contribute to photochemical smog. High levels of xylenes have been reported in groundwater associated with localized pollution from underground tanks and pipes, but the environmental significance of such values is difficult to assess. For the aquatic environment, the most sensitive toxicity test, based on measured concentrations, yielded an LC50 for Daphnia magna of 1 mg/litre ( o-xylene). This value is more than 10 000 times higher than mean background concentrations in surface water, which are generally less than 0.1 µg/litre for each isomer. The lowest LC50 is still over 30 times higher than the highest single measured concentration of total xylenes in the most polluted area. The exposure/toxicity ratio will be much higher for mean concentrations in polluted areas. On the basis of rapid volatilization and degradation of xylenes and their low to moderate toxicity, the overall risk to the aquatic environment can therefore be considered low. It should be noted, however, that very much higher levels have been measured around discharges from oil production sites, and higher levels are also possible if spillage occurs. The likely route of exposure for birds in the environment is via food such as fish. The only acute toxicity test on birds was carried out on 14-day old Japanese quail and gave a 5-day LC50 of > 5000 mg/kg diet. Based on food consumption and body weight, an LD50 for the quail of > 1746 mg/kg body weight can be calculated. Using this data an estimated LC50 for a fish-eating bird (kingfisher) based on body weight and food consumption can be calculated. LC50 (mg/kg dry weight diet) = Test species LD50 (mg/kg) × body wt (kg) food consumption (kg) The estimated LC50 for the fish-eating bird is > 7990 mg/kg diet. The highest water concentration (30 µg/litre) multiplied by the highest theoretical bioconcentration factor (158) gives a worst case residue level in fish of 4.7 mg/kg. It should be noted that the bioconcentration factor does not take into account degradation or metabolism. Comparing this value to the estimated LC50 value gives a Toxicity Exposure Ratio (TER) of > 1700. Therefore, the risk to fish-eating birds is very low. 11. CONCLUSIONS Humans are exposed to xylene mainly by inhalation. This compound does not accumulate significantly in the human body. Acute exposure to high concentrations can result in CNS effects in human. There have been no long-term controlled studies or epidemiological studies with exposure to xylene alone. The chronic toxicity appears to be relatively low in laboratory animals. There is suggestive evidence, however, that chronic CNS effects may occur in animals at moderate concentrations of xylene. Xylene appears not to be a mutagen or a carcinogen. The critical end-point is developmental toxicity. Based on this end-point, the recommended guidance value for xylene in air for the general population is 0.87 mg/m3 (0.2 ppm). This value is higher than the concentrations to which the general population is exposed. The xylene isomers are non-persistent chemicals, being readily degraded in the atmosphere, soil and water. It should be noted that o-xylene appears to biodegrade only in the presence of other carbon sources and at a reduced rate compared to the other isomers. The photooxidation reactions of the xylene isomers in the atmosphere may contribute to photochemical smog. It can be concluded that xylenes are unlikely to cause problems in aquatic ecosystems except near to localized industrial discharges and spillage incidents. The risk to birds from xylene exposure is low. 12. FUTURE RESEARCH There is little information on the long-term effects of xylene in humans and, specifically, no dose-response or dose-effect data are available. Epidemiological studies of populations occupationally exposed to xylene should be encouraged. In this context the use of xylene metabolites in urine as a marker of exposure can be of special value because the method determines the internal doses that individuals receive via all routes of exposure. Because xylene has acute effects on CNS, epidemiological studies should address the CNS as a potential target organ. Moreover, since ethylbenzene is almost invariably one of the components in solvent mixtures at the workplace, study designs that address possible interactions between xylene and other solvent components are desirable. Animal studies are needed to address biochemical, functional and morphological evidence of chronic neurotoxicity and potential effects on fertility. In addition, there is a need for further studies on developmental toxicity to assess the dose-response relationship and to estimate the NOAEL, especially for developmental neurotoxicity. Further studies are needed to determine the effect on hearing impairment in order to determine the NOAEL. The relationship between the dose level and the length of the exposure period should also be investigated. The effect of exposure to xylene together with noise should be studied. 13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES The International Agency for Research on Cancer (IARC) has evaluated the carcinogenicity of xylene. 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Zimmerman SW, Groehler K, & Beirne GJ (1975) Hydrocarbon exposure and chronic glomerulonephritis. Lancet, 2: 199-201. RESUME Le xylčne est un hydrocarbure aromatique qui existe sous trois formes: les isomčres ortho, méta et para. Le xylčne de qualité technique est un mélange des trois isomčres qui contient en outre un peu d'éthylbenzčne. En 1984, la production mondiale de xylčne était estimée ą 15,4 millions de tonnes. A la température ambiante, le xylčne se présente sous la forme d'un liquide incolore d'odeur aromatique. La tension de vapeur est comprise entre 0,66 et 0,86 kPa pour les trois isomčres. Environ 92% des mélanges de xylčnes sont incorporés ą l'essence. On les utilise aussi comme solvants, en particulier dans les peintures et les encres d'imprimerie. La majeure partie du xylčne libéré dans l'environnement passe directement dans l'atmosphčre. Les trois isomčres y sont rapidement décomposés, principalement par photooxydation. Ils se volatilisent tous les trois rapidement ą partir de l'eau. Dans le sol et dans l'eau, les isomčres méta et para subissent une biodégradation aisée dans des conditions variées d'aérobiose et d'anaérobiose; en revanche, l'isomčre ortho est plus persistant. Les données limitées dont on dispose indiquent que les xylčnes isomčres s'accumulent peu chez les poissons et les invertébrés. Une fois que l'exposition a cessé, ils sont assez rapidement éliminés par les organismes aquatiques. Les concentrations moyennes de fond des trois xylčnes dans l'air ambiant se situent autour de la valeur caractéristique de 1 µg/m3, mais dans les banlieues elles atteignent 3 µg/m3 environ. On a mesuré des valeurs plus élevées en zone urbaine et industrielle, les moyennes allant cette fois jusqu'ą 500 µg/m3. Toutefois, la concentration est en général inférieure ą 100 µg/m3. On estime que l'exposition journaličre de la population par la voie respiratoire est de 70 µg en milieu rural et de 2 000 µg en milieu urbain. Dans l'eau de boisson, la concentration varie de zéro ą 12 µg/litre. Les données concernant la concentration dans les denrées alimentaires sont trop limitées pour que l'on puisse évaluer l'exposition journaličre par voie orale. Dans les eaux superficielles, la concentration moyenne de fond des xylčnes est généralement inférieure ą 0,1 µg/litre. Cependant, on a mesuré des valeurs beaucoup plus élevées dans des zones industrielles et plus particuličrement celles oł sont implantées des industries pétroličres (jusqu'ą 30 µg/litre dans les eaux polluées et jusqu'ą 2 000 µg/litre ą proximité des conduites de décharge). Des valeurs analogues ont été observées dans les eaux souterraines, ces valeurs élevées pouvant źtre attribuées dans certains cas ą une pollution locale par des réservoirs et des canalisations enterrées. Aprčs exposition par la voie respiratoire, la dose inhalée est retenue ą 60% environ dans les poumons. La métabolisation est efficace puisque le xylčne est transformé ą 90% en acide méthylhippurique, lequel est ensuite excrété dans les urines. Le xylčne ne s'accumule pas en quantité importante dans l'organisme humain. Chez l'homme, une exposition aiguė ą du xylčne sous forte concentration peut avoir des effets sur le systčme nerveux central et provoquer une irritation. Ces effets n'ont toutefois pas donné lieu ą des études contrōlées ni ą des études épidémiologiques ą long terme. Chez les animaux de laboratoire, la toxicité chronique se révčle faible. On a cependant de bonnes raisons de penser que sous concentration modérée, le xylčne pourrait avoir des effets sur le SNC chez l'animal. Le xylčne ne s'est révélé ni mutagčne ni cancérogčne. Le point d'aboutissement toxicologique essentiel concerne l'effet nocif que le xylčne exerce sur le développment. On l'a mis en évidence chez le rat ą partir d'une concentration de 870 mg/m3 (200 ppm). Compte tenu de cela, la valeur-guide recommandée pour la concentration maximale de xylčne dans l'air a été fixée ą 0,87 mg/m3 (0,2 ppm). Les xylčnes isomčres sont faiblement ą modérément toxiques pour les organismes aquatiques. Chez les invertébrés, c'est l' o-xylčne qui a la Cl50 la plus faible (1 mg/litre pour Daphnia magna). Chez les poissons, la CL50 la plus faible est également celle de l' o-xylčne (7,6 mg/litre chez la truite arc-en-ciel, par mesure de concentration). Des valeurs de 7,9 et 1,7 mg/litre ont été obtenues, respectivement pour le m- et le p-xylčne, dans le cas de la perche commune (d'aprčs la concentration nominale). On ne dispose que de données limitées au sujet de l'exposition chronique des organismes aquatiques aux xylčnes, mais, quoi qu'il en soit, la volatilisation rapide de ces composés la rend peu probable. Le xylčne ne présente qu'une faible toxicité aiguė pour les oiseaux. RESUMEN El xileno es un hidrocarburo aromįtico del que hay tres formas isoméricas: orto, meta y para. El xileno de calidad técnica contiene una mezcla de los tres isómeros y algo de etilbenceno. Se estima que la producción mundial fue de 15,4 millones de tone-ladas en 1984. La presión de vapor estį comprendida entre 0,66 y 0,86 kPa para los tres isómeros. Aproximadamente un 92% de las mezclas de xilenos se combinan con el petróleo. El producto se emplea también en diversos disolventes, en particular en las industrias de fabricación de pinturas y de tintas de imprenta. La mayor parte del xileno liberado en el medio ambiente pasa directamente a la atmósfera. En ésta los isómeros de xileno se degradan con facilidad, principalmente por fotooxidación. Los tres isómeros se volatilizan rįpidamente en la atmósfera a partir del agua. En el suelo y el agua los isómeros meta y para se biodegradan fįcilmente en una amplia variedad de condiciones aerobias y anaerobias, pero el isómero orto es mįs persistente. Las limitadas pruebas disponibles parecen indicar que la bioacumulación de los isómeros de xileno por los peces y los invertebrados es baja. La eliminación del xileno de los organismos acuįticos es bastante rįpida a partir del momento en que se interrumpe la exposición. Normalmente los niveles basales medios de los tres isómeros de xileno en el aire ambiente son de aproximadamente 1 µg/m3, pero en zonas suburbanas se hallan en torno a 3 µg/m3. Se han detectado concentraciones mayores en zonas urbanas e industrializadas, con niveles medios de hasta 500 µg/m3. No obstante, las concentraciones son por lo general inferiores a 100 µg/m3. La exposición diaria por inhalación estimada en la población general es de 70 µg en zonas rurales y de menos de 2000 µg en zonas urbanas. La concentración en el agua potable estį comprendida entre valores indetectables y 12 µg/litro. Los datos disponibles sobre la concentración en los alimentos son insuficientes para poder estimar la exposición oral diaria. Las concentraciones basales medias de xilenos en aguas superficiales son generalmente inferiores a 0.1 µg/litro. Sin embargo se han hallado valores mucho mįs altos en zonas industriales y en zonas vinculadas a la industria petrolera (hasta 30 µg/litro en aguas contaminadas y hasta 2000 µg/litro en las proximidades de tuberķas de desagüe). Se ha informado del hallazgo de niveles basales similares en aguas subterrįneas, aunque se han detectado también concentraciones elevadas, atribuidas a contaminación localizada a partir de tanques de almacenamiento y tuberķas subterrįneos. Tras la exposición por inhalación la retención pulmonar es de un 60% de la dosis inhalada. El xileno es metabolizado eficientemente. Mįs del 90% se biotransforma en įcido metilhipśrico, que se excreta por la orina. El xileno no se acumula de forma significativa en el organismo humano. La exposición aguda a altas concentraciones de xileno puede afectar al SNC y causar irritación en el hombre. Sin embargo, no se han llevado a cabo ni estudios controlados a largo plazo en el ser humano ni estudios epidemiológicos. La toxicidad crónica parece relativamente baja en animales de laboratorio. Hay indicios, no obstante, de que concentraciones moderadas de xileno pueden tener efectos crónicos sobre el SNC en animales. El xileno no parece tener efectos mutįgenos ni carcinógenos. El parįmetro crķtico es la toxicidad para el desarrollo, demostrada a niveles de exposición de 870 mg/m3 (200 ppm) en la rata. Teniendo en cuenta este parįmetro, la concentración indicativa recomendada para el xileno en el aire es de 0.87 mg/m3 (0,2 ppm). Los isómeros de xileno poseen una toxicidad entre moderada y baja para los organismos acuįticos. En invertebrados la CL50 mįs baja, calculada a partir de las concentraciones medidas, es de 1 mg/litro para el o-xileno (Daphnia magna). Los valores mįs bajos de CL50 detectados en peces son de 7,6 mg/litro para el o-xileno (trucha arco iris; segśn las concentraciones medidas), y de 7,9 y 1,7 mg/litro para los m- y p-xilenos respectivamente (ambos para la lubina estriada; segśn las concentraciones nominales). La información disponible respecto a la exposición crónica de organismos acuįticos a los xilenos es limitada; no obstante, su rįpida volatilización hace improbable la exposición crónica en el agua. La toxicidad aguda del xileno para las aves es baja.
See Also: m-Xylene (CHEMINFO) m-Xylene (ICSC) Mixed xylenes (CHEMINFO) o-Xylene (CHEMINFO) o-Xylene (ICSC) p-Xylene (CHEMINFO) Xylene (IARC Summary & Evaluation, Volume 71, 1999) Xylene (PIM 565)