UNITED NATIONS ENVIRONMENT PROGRAMME INTERNATIONAL LABOUR ORGANISATION WORLD HEALTH ORGANIZATION INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 193 Phosgene 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. Environmental Health Criteria 193 First draft prepared at the National Institute of Health Sciences, Tokyo, Japan, and the Institute of Terrestrial Ecology, Monk's Wood, 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, the International Labour Organisation, and the World Health Organization. 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. WHO Library Cataloguing in Publication Data Phosgene (Environmental health criteria ;193) 1.Phosgene - toxicity 2.Phosgene - adverse effects 3. Environmental exposure I.Series ISBN 92 4 157193 4 (NLM Classification: QV664) 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 PHOSGENE PREAMBLE ABBREVIATIONS 1. SUMMARY 1.1 Identity, physical and chemical properties, and analytical methods 1.2 Uses and sources of human and environmental exposure 1.3 Environmental transport, distribution and transformation 1.4 Environmental levels and human exposure 1.5 Kinetics and metabolism 1.6 Effects on experimental animals and in vitro test systems 1.6.1 Single and short-term exposures 1.6.2 Non-pulmonary effects 1.7 Effects on humans 1.8 Effects on organisms in the environment 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS 2.1 Identity 2.2 Physical and chemical properties 2.3 Analytical methods 2.4 Conversion factors 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1 Natural occurrence 3.2 Anthropogenic sources 3.2.1 Production levels and processes 3.2.2 Environmental processes 3.2.3 Uses 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION 4.1 Transport and distribution between media 4.2 Abiotic degradation 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1 Environmental levels 5.1.1 Air 5.1.2 Water 5.1.3 Soil 5.1.4 Food and feed 5.2 General population exposure 5.3 Occupational exposure 5.3.1 Manufacture and use 5.3.2 Non-manufacturing occupations 6. KINETICS AND METABOLISM 6.1 Absorption 6.2 Distribution 7. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS 7.1 Single and short-term inhalation exposures 7.2 Skin and eye irritation; sensitization 7.3 Long-term exposure 7.4 Reproductive and developmental toxicity 7.5 Mutagenicity and related end-points 7.6 Carcinogenicity 7.7 Immunotoxicity 7.8 Mechanism of toxicity. 8. EFFECTS ON HUMANS 8.1 General population and occupational exposure 8.2 Case reports - individual accidents 8.3 Epidemiological studies 9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD 10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT 10.1 Evaluation of human health risks 10.1.1 Exposure 10.1.2 Health effects 10.1.2.1 Evaluation of animal data 10.1.2.2 Evaluation of human data 10.1.3 Guidance value 10.2 Evaluation of effects on the environment 11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH 11.1 Conclusions 11.2 Recommendations for protection of human health 12. FURTHER RESEARCH 13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES REFERENCES RESUME ET CONCLUSIONS RESUMEN Y CONCLUSIONES 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 Châtelaine, Geneva, Switzerland (telephone no. + 41 22 - 9799111, fax no. + 41 22 - 7973460, E-mail email@example.com). * * * 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. * * * The Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Germany, provided financial support for this publication. 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 PHOSGENE Members Dr D. Anderson, British Industry Biological Research Institute (BIBRA) Toxicology International, Carshalton, Surrey, United Kingdom Dr R. Chhabra, Environmental Toxicology Program, Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA Dr H. Ellisa, Epidemiology Department, Rohm & Haas, Bristol, Pennsylvania, USA Dr B. Gilbert, FarManguinhos, FIOCRUZ, Institute of Technology and Pharmacology, Ministry of Health, Manguinhos, Rio de Janeiro, Brazil ( Chairman) Professor M. Jakubowski, Occupational and Environmental Hygiene Division, Nofer Institute of Occupational Medicine, Lodz, Poland Dr S.K. Kashyap, National Institute of Occupational Health, Meghani Nagar, Ahmedabad, India ( Vice-chairman) Dr R. Liteplo, Environmental Health Directorate, Health Protection Branch, Environmental Health Centre, Tunney's Pasture, Ottawa, Ontario, Canada Dr E. E. McConnell, Laurdane Estates, Raleigh, North Carolina, USA ( Co-rapporteur) Dr H. Naito, Ibaraki Prefecture University of Health Sciences, Amimachi, Inashikigun, Ibaraki, Japan __________ a Invited, but unable to attend. Dr W. Popp, Universitatsklinikum Essen, Institute for Health and Occupational Medicine, Essen, Germany Dr R. Sram, Laboratory of Genetic Ecotoxicology, Institute of Experimental Medicine, Videnska, Prague, Czech Republic Dr Shou-Zheng Xue, Toxicology Programme, Shanghai Medical University, Shanghai, People's Republic of China Secretariat Dr G. C. Becking, Team Leader, IPCS/IRRU, World Health Organization, Research Triangle Park, North Carolina, USA Ms R. Gomes, Health Canada, Environmental Health Directorate, Tunney's Pasture, Ottawa, Ontario, Canada ( Co-rapporteur) ENVIRONMENTAL HEALTH CRITERIA FOR PHOSGENE A WHO Task Group on Environmental Health Criteria for Phosgene and Selected Chloroalkyl Ethers met at the British Industrial Biological Research Association (BIBRA) Toxicology International, Carshalton, Surrey, United Kingdom, from 18 to 23 March 1996. Dr D. Anderson opened the meeting and welcomed the participants on behalf of the host institute. Dr G.C. Becking, IPCS, welcomed the participants on behalf of Dr M. Mercier, Director of the IPCS, and the three 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 phosgene. Financial support for this Task Group was provided by the United Kingdom Department of Health as part of its contribution to the IPCS. Dr E.E. McConnell, Raleigh, North Carolina, USA, prepared the first draft of this monograph. The draft reviewed by the Task Group, which contained the comments received following circulation of the draft monograph to the IPCS Contact Points for Environmental Health Criteria monographs, was prepared by the Secretariat. Dr G.C. Becking (IPCS, Central Unit, Inter-regional Research Unit) and Dr P.G. Jenkins (IPCS, Central Unit, Geneva) were responsible for the overall scientific content and technical editing, respectively. The efforts of all who helped in the preparation of the document are gratefully acknowledged. ABBREVIATIONS CI confidence interval L(CT)50 median lethal concentration-time product LFP lavage fluid protein MDI methylene-diphenyl diisocyanate Nk natural killer OES occupational exposure standard PMN polymorphonuclear leukocyte ppb parts per billion ppm parts per million ppt parts per trillion PVC polyvinyl chloride SMR standardized mortality ratio TDI toluene diisocyanate TLV threshold limit value TWA time-weighted average 1. SUMMARY 1.1 Identity, physical and chemical properties, and analytical methods Phosgene is a highly reactive colourless gas at room temperature and ambient pressure, and has a suffocating odour similar to mouldy hay. The odour may be detected between 1.6 and 6 mg/m3. Analytical methods are available for the detection of phosgene in air and for use in industrial hygiene programmes that measure total dose (e.g., paper tape monitors). 1.2 Uses and sources of human and environmental exposure More than 99% of the phosgene produced is used on-site in closed systems. It is produced by reacting equimolar amounts of anhydrous chlorine and carbon monoxide in the presence of a carbon catalyst. World production has been estimated to be greater than 3 million tonnes. Environmental phosgene levels arise from industrial emissions and thermal degradation of some chlorinated solvents and chlorinated polymers. However, a significant source of environmental phosgene is the photochemical oxidation of chloroethylenes such a tri- and tetraethylene. 1.3 Environmental transport, distribution and transformation Because of its high reactivity, inter-compartmental transport of phosgene is expected to be limited. Removal of phosgene from ambient air occurs by heterogeneous decomposition (surface catalysis) and slow gas-phase hydrolysis. Long-range transport takes place and diffusion from the troposphere to the stratosphere is believed to lead to more rapid photolytic degradation of phosgene. 1.4 Environmental levels and human exposure Human exposure in both the general population and occupational setting is primarily by inhalation. The average level of phosgene in ambient air may range from approximately 80 to 130 ng/m3 although few data are available. In view of the varied industrial hygiene practices worldwide it is impossible to give an exposure figure for workers manufacturing or using phosgene or for fire-fighters. At present the Threshold Limit Values (time-weighted average) in 15 countries range from 0.4 and 0.5 mg/m3. Levels of phosgene in water, soil and food have not been reported. 1.5 Kinetics and metabolism There are very few data on the absorption, metabolism, distribution and fate of phosgene. The primary route of exposure is by inhalation, the gas penetrates into the tissues of the respiratory tract, and so only minimal amounts of phosgene are distributed in the body. The very short half-life (0.026 seconds) in aqueous solutions precludes a significant retention of phosgene in the body. No information on the metabolism of phosgene has been reported. The hydrolyic products of phosgene, i.e. hydrochloric acid and carbon dioxide, are disposed of by the body through normal physiological processes. Phosgene exerts its toxicity through acylation of proteins, as well as through the production of hydrochloric acid. The amino, hydroxyl and sulfhydryl groups in the proteins appear to be the target for acylation leading to marked inhibition of several enzymes related to energy metabolism and a breakdown of the blood:air barrier. 1.6 Effects on experimental animals and in vitro test systems 1.6.1 Single and short-term exposures In all species studied, the lung is the major target organ. The L(CT)50 varies from 900 mg/m3-min (225 ppm-min) in the mouse to 1920 mg/m3-min (480 ppm-min) in the guinea-pig. An L(CT)50 of 1000 mg/m3-min (250 ppm-min) was reported in the monkey. In all species the characteristic pathological feature is the delayed clinical manifestation of pulmonary oedema, which is dose-dependent. Pathological changes in the terminal bronchioles and alveoli at low concentrations are typical of a pulmonary irritant, whereas at higher exposures pulmonary oedema occurs, leading to interference with gas exchange and death. No long-term exposure studies of phosgene have been reported. One study in rats showed that a single phosgene exposure of 2 mg/m3 for 4 h can result in decreased pulmonary immunocompetence as measured by the natural killer activity of pulmonary cells. No effects were seen at an exposure level of 0.4 mg/m3 for 4 h. Two other studies of the effects of single exposures of phosgene on pulmonary immunocompetence in rats and mice have been reported. In rats infected with influenza virus after a 4-h exposure to 4 mg phosgene/m3, there was a 10-fold increase in viral titre 1 day post-infection, which remained significantly elevated for 4 days. Furthermore, in rats exposed to phosgene levels between 0.2 and 4 mg/m3 for 4 h, a marked decrease in prostaglandin E2 and leukotrienes was noted at exposure levels of 0.4 mg/m3 or more, with a decrease in the number of alveolar macrophages and an increase in the number of neutrophils observed at 0.4 mg/m3. In a host- resistance assay, where mice were exposed to levels of phosgene between 0.04 and 0.4 mg/m3 for 4 h, an increase in mortality from Streptococcus zooepidemicus infection or an increased number of B16/BL6 melanoma lung tumours was noted at levels of 0.1 mg/m3 or more. Pulmonary bacterial clearance was reduced in rats exposed to 0.4 mg/m3 (0.1 ppm) phosgene for 6 h or to 0.4 mg/m3 (0.1 ppm) for 6 h/day, 5 days/week for 4 to 12 weeks. This effect was reversible following termination of exposure. 1.6.2 Non-pulmonary effects Phosgene exposure can result in eye and skin irritation. Studies concerning the sensitization potential of phosgene have not been found in the literature. No data are available on the reproductive and developmental effects of phosgene. No adequate data are available for the assessment of the mutagenicity or carcinogenicity of phosgene. 1.7 Effects on humans The target organ in humans, as in experimental animals, is the lung. After exposure to phosgene levels between 120 and 1200 mg/m3-min, three distinct clinicopathological phases have been reported. The initial phase consists of pain in the eyes and throat and tightness in the chest, often with shortness of breath, wheezing and coughing; hypotension, bradycardia and rarely sinus arrhythmias can occur. The second or latent phase, which is often asymptomatic, can last as long as 24 h depending upon the level and duration of exposure. In the third phase, pulmonary oedema may develop, leading to death in some cases. Populations exposed to phosgene after industrial accidents have reported a wide variety of symptoms, including headache, nausea, cough, dyspnoea, fatigue, pharyngeal pain, chest tightness and pain, intense pain in the eye and severe lacrimation. In one study pulmonary oedema occurred after a latent phase of 48 h. The effects of long-term exposure to phosgene have been studied in three groups of workers at two facilities, i.e., a phosgene production plant and an uranium processing facility. In both facilities, only limited air sampling or personal monitoring was carried out, and worker exposures were only estimates. An examination of the medical records of all 326 workers in the phosgene production facility who were potentially exposed to phosgene (up to 0.5 mg/m3, with some excursions above this value; average 0.01 mg/m3) did not yield any chronic lung problems or increased mortality from respiratory disease compared to a group of 6228 controls. However, the lack of detail in the report on both exposure and effects makes it difficult to draw firm conclusions from this study. Two groups of workers were studied at the uranium processing plant: a cross-section of 699 workers from the over 18 000 employed during the period, with potential exposure to phosgene levels below 0.4 mg/m3 (and 4 or 5 daily short-term excursions to > 4 mg/m3); and a group of 106 workers known to have been involved in accidents and exposed to levels above 200 mg/m3-min. In the group exposed chronically to low levels of phosgene, an examination of death certificates did not indicate an increased mortality from all causes or from respiratory disease or lung cancer. In the group involved in chemical accidents no increase in deaths from all causes was reported. There were no lung cancer deaths but there was a slight increase in the number of deaths from respiratory diseases. In view of the lack of exposure data and the methodological characteristics of this study the conclusions regarding the chronic effects of phosgene that can be drawn are limited. 1.8 Effects on other organisms in the laboratory and field No information concerning the effects of phosgene on organisms in the environment has been reported. 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS 2.1 Identity Molecular formula: COC12 Chemical structure: CI \ C = O / CI Common Synonyms: carbonic acid dichloride, carbonyl chloride, chloroformyl chloride, carbon oxychloride IUPAC and CAS names: carbonic dichloride CAS Registry number: CAS 75-44-5 RTECS Registry number: SY5600000 UN Transport number: 1076 2.2 Physical and chemical properties Phosgene is a colourless nonflammable gas at room temperature and ambient pressure. It has a suffocating odour and a smell reminiscent of mouldy hay (Budavari, 1996). The recognition of the odour of phosgene occurs at levels > 6 mg/m3 (1.5 ppm), although some trained workers are capable of perceiving the odour at a level of 0.4 mg/m3 (0.1 ppm). The physical and chemical properties are summarized in Table 1. Table 1. Physical and chemical properties of phosgenea Colour colourless Relative molecular mass 98.92 Physical state gas Melting point -127.8°C Boiling point 7.56°C Vapour pressure (20°C) 161.6 kPa Relative vapour density (air = 1)3.42 Relative density, 20°C (water = 1)1.4 Solubility in water slight, reacts with water Solubility in organic solvents reacts with ethanol, very soluble in benzene, toluene, acetic acid, and most liquid hydrocarbons a From: Schneider & Diller (1989); Verschueren (1983); Budavari (1996) 2.3 Analytical methods A number of techniques may be used to determine phosgene concentrations in air. These include passive dosimetry (Moore & Matherne, 1981; Mathern et al., 1981), manual colorimetry (NIOSH, 1976), automated colorimetry (US EPA, 1986; Dangwal, 1994), gas chromatography (Singh, 1976; Tuggle et al., 1979), infrared spectroscopy (Esposito, 1977) and ultraviolet spectrophotometry (Crummett & McLean, 1965). In addition, paper tape monitors capable of detecting 5 µg/m3 have been described (Hardy, 1982). A summary of these methods is presented in Table 2. Table 2. Sampling and analysis of phosgene in aira Sampling Analytical methodb Limit of detection Sample Comments Reference methodb (range) size Passive Direct reading (8-400 mg/m3-min) - Concentration- Moore & dosimetry colorimetric reaction time relationship Matherne with NBP in breathing zone (1981) Air through Measure colour at (0.2 - 100 mg/m3) 1 litre/min Too slow NIOSH (1976) impinger 475 nm for 25 min response for containing DEP continuous solution of NBP monitoring and BA Air bubbled into Automated colorimetry 0.004 mg/m3 1 litre/min Response time of US EPA (1986) flowing stream of at reagent flow rate of (0-4 mg/m3) for 20 min 20 min too long NBP-BA-DEP 0.2 ml/min for continuous monitoring Air through Derivative determined 0.04 mg/m3 1 litre air Extremely Wu & Gaind impinger by reverse-phase HPLC sample sensitive but (1993) containing needs highly tryptamine trained staff and equipment Table 2 (contd). Sampling Analytical methodb Limit of detection Sample Comments Reference methodb (range) size Direct sample Gas-chromatography 0.5 ml Extremely Singh (1976) injection, - electron capture < 0.08 mg/m3 injection sensitive, needs Tuggle et al. continuous - aluminium columns < 0.08 - 20 mg/m3 highly trained (1979) sampling didecyl phthalate on staff and chromosorb p equipment Air is drawn Infrared spectroscopy, 0.1 mg/m3 2 to 5 Can be used as a Esposito et al. directly into comparison of (0.1 to 1200 litre/min continuous (1977) spectrophotometer absorbance at 11.8 µm mg/m3) monitor for and reference ambient levels of wavelength of 11.2 µmn phosgene using 20 m variable path length cell a Proper medical treatment for those exposed to phosgene will depend on the concentration and length of exposure. Therefore, any procedure used for monitoring ambient and workplace levels must give information on both parameters, preferably on a continuous basis, since a latent period of 2-24h may occur between exposure and any warning symptoms. b NBP = 4,4 -nitrobenzyl pyridine DEP = diethyt phthalate BA = N-benzylalanine HPLC = high performance 2.4 Conversion factors 1 ppm = 4.05 mg/m3 1 mg/m3 = 0.25 ppm at 25°C and 101.3 kPa 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1 Natural occurrence Phosgene is not known to occur naturally. 3.2 Anthropogenic sources 3.2.1 Production levels and processes Phosgene is produced by reacting equimolar amounts of anhydrous chlorine and carbon monoxide in the presence of a carbon catalyst (Schneider & Diller, 1989). The great majority is used directly in a closed system. It is difficult to give accurate production figures because more than 99% of phosgene production is for on-site use (Schneider & Diller, 1989). However, phosgene is manufactured in most industrialized countries. Approximately 37% of the world's production is in the USA (about 1 million tons); in 1989 European phosgene production was approximately 1.2 million tonnes (Schneider & Diller, 1989). 3.2.2 Environmental processes Phosgene in ambient air may arise from three sources: a) direct emissions during its manufacture, handling, use and disposal; b) thermal decomposition, in the presence of air, of chlorinated hydrocarbons, e.g., solvents such as chloroform, methylene chloride (Snyder et al., 1992) and 1,2-dichloropropane (IPCS, 1993) and polymers such as polyvinyl chloride (PVC); c) photooxidation of chlorinated hydrocarbons, particularly chloroform and the chloroethylenes (Rinzema, 1971; Singh, 1976; Gay et al., 1976; Birgesson, 1987). The thermal degradation of chlorinated hydrocarbons can occur as a result of combustion of these materials during waste disposal, in fires, and during welding in situations where PVC plastics are degraded (Rinzema, 1971; Birgesson, 1982). Firefighters and welders are at particular risk from these sources of phosgene. A significant contribution to ambient air levels of phosgene is the photooxidation of chloroethylenes, particularly tri- and tetra- chloroethylene (Singh, 1976; Gay et al. 1976). It has been estimated that such reactions may result in the worldwide formation of 350 000 tonnes of phosgene per year (Singh, 1976). 3.2.3 Uses Initially important as an agent of chemical warfare, phosgene is now widely used as a chemical intermediate, most often at the point of production. The major use is in the production of aromatic diisocyanates such as methylene diphenyl diisocyanate (MDI) and toluene diisocyanate (TDI), which are used to produce polyurethane foams and other polymers. Worldwide about 80% of phosgene is used for TDI and MDI production. Other major uses of phosgene include the production of polycarbonate, aliphatic diisocyanates, monoisocyanates and chloroformic esters and urethanes (Schneider & Diller, 1989; Borak, 1991). Phosgene is also used in the manufacture of some agrochemicals, in the pharmaceutical industry, and metallurgy (US NLM, 1995). 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION 4.1 Transport and distribution between media Phosgene can enter the atmosphere in the form of industrial emissions or from the degradation of chlorohydrocarbons (section 3.2.2). Detectable levels have been found in ambient air (section 5.1.1). However phosgene is unlikely to be detectable in soil and vegetation owing to heterogeneous decomposition (section 4.2). In water, phosgene is rapidly degraded to hydrochloric acid and carbon dioxide (Butler & Snelson., 1979), the half-life in aqueous solution being 0.026 seconds (Manogue and Pigford, 1969). In the atmosphere, even at high humidity levels, phosgene is only slowly decomposed (Noweir et al., 1973; US EPA, 1986). The half-life by homogeneous gas-phase hydrolysis of 4 g /m3 phosgene (1 ppb) in nitrogen (at sea-level pressure, 25 C and with water vapour at a pressure of 10 Torr) has been calculated to be 113 years (range 20 to 630 years) (Butler & Snelson, 1979). Reaction rates with activated oxygen and hydroxyl radicals are also slow (Singh, 1976). Phosgene is, therefore, likely to be persistent in the atmosphere and subject to long-range transport. Diffusion to the stratosphere leads to more rapid degradation by photolysis (Singh, et al., 1977). 4.2 Abiotic degradation Reaction with molecules having an active hydrogen atom (e.g., water, primary and secondary alcohols, thiols and amines) does occur, forming hydrochloric acid, carbon dioxide, and carbonic acid derivatives (Butler & Snelson, 1979; Schneider & Diller, 1989), but phosgene reacts very slowly in the gas phase with photochemically produced hydroxyl radicals (Singh, 1976).Removal of phosgene from ambient air occurs by two major pathways, i.e. heterogeneous decomposition (Noweir et al., 1973) and liquid-phase hydrolysis (Singh et al., 1977). At normal ambient temperatures the gas-phase hydrolysis is the major pathway for phosgene degradation (Singh et al., 1977). However, even contact with soil particles and vegetation at ambient temperatures enhances the rate of phosgene degradation (Noweir et al., 1973). 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1 Environmental levels 5.1.1 Air It has been suggested that the primary source of atmospheric levels of phosgene is from the thermal degradation and photo- degradation of chlorinated solvents such as tri- and tetrachloroethylene and PVC (Singh, 1976). Direct emissions from the production and use of the chemical play a minor role and would most likely affect the air levels only near the factory. Phosgene levels in ambient air at four locations in California, USA, were reported by Singh et al. (1977). Multiple samples (10 to 257) were taken on a 24-h basis from a single location in each area. In one rural area an average level of 87 ng/m3 (21.7 ppt) was reported. The average levels found in three urban areas were 117 ng/m3 (29.3 ppt), 121 ng/m3 (30.3 ppt) and 129 ng/m3 (31.8 ppt), with a peak level in one sample of 244 ng/m3 (61.0 ppt). In three other cities in the USA the average level of phosgene in ambient air was reported to be less than 80 ng/m3 (20 ppt) (Singh et al., 1981). 5.1.2 Water There are no data on levels of phosgene in water, since hydrolysis precludes significant accumulation in this medium. 5.1.3 Soil Data on levels of phosgene in soil are not available, since rapid breakdown on contact with solid surfaces and moisture prevents a significant accumulation in this medium (Noweir et al., 1973). 5.1.4 Food and feed Although no data are available, the lack of stability in the presence of liquid-phase water, solid surfaces, and alcohols and or amines in foods makes contamination of food by phosgene unlikely (see sections 4.1 and 4.2). 5.2 General population exposure The general population is exposed to only very low levels (in the ng/m3 range) of phosgene and this is almost entirely via contaminated urban air. The origin of this phosgene is from decomposition of other chlorinated compounds or, in isolated circumstances, from the emissions of an industrial enterprise making or using phosgene without carrying out appropriate industrial hygiene practices. Based on the range of average concentrations (< 80-129 ng/m3) given in section 5.1.1, the estimated total daily intake of phosgene may range from < 1.6 to 2.6 g, assuming a daily respiratory intake of 20 m3 air. Much higher levels of phosgene exposure are possible during home use of chemicals such as methylene chloride under conditions where the temperature is sufficiently high to lead to degradation of this chemical (Snyder et al., 1992). 5.3 Occupational exposure 5.3.1 Manufacture and use Occupational exposure limits (8- or 10-h TLV) in some 15 countries range between 0.4 and 0.5 mg/m3 (ILO, 1991). Based upon animal data, the United Kingdom has proposed an OES (8-h TWA) of 0.08 mg/m3 (0.02 ppm) and an STEL of 0.24 mg/m3 (0.06 ppm) (HSE, 1995). It is difficult to report actual values in individual factories worldwide since levels will vary greatly depending upon the level of industrial hygiene practiced in any particular factory. However, even early monitoring reports indicated that exposures were generally below the recommended TLV. In a few cases exposure levels above 0.4 mg/m3 have been reported (Levina et al., (1966). In a factory manufacturing phosgene, personal samplers detected levels up to 0.08 mg/m3 (average 0.012 mg/m3), whereas fixed position samplers (total of 56) showed levels between non-detectable and 0.52 mg/m3 in 51 samples, with excursions in a few samples to about 71 mg/m3 (NIOSH, 1976). More recent monitoring data are lacking. 5.3.2 Non-manufacturing occupations Firefighters and workers engaged in welding and building trades are at risk from the phosgene formed by the thermal degradation of chlorinated hydrocarbons and PVC. The pyrolysis of Freon present in commercial refrigeration units (Birgesson, 1982), tri- and tetrachloroethylene (Rinzema, 1971; Andersson et al., 1975), PVC (Brown & Birky, 1980) and methylene chloride (Snyder et al., 1992) have all been shown to result in toxic levels of phosgene. However, actual levels in the area of work or the breathing zone were not quantified in these studies. 6. KINETICS AND METABOLISM Because of the physico-chemical properties of phosgene, the kinetics and metabolism of phosgene in animals should be similar if not identical to those found in humans. However, because of the highly toxic nature of phosgene, human experimental data appropriate for use in this monograph does not exist. 6.1 Disposition of phosgene There are very few data on absorption, metabolism, distribution and fate of phosgene. The primary route of exposure is by inhalation. The gas penetrates into the tissues of the respiratory tract, and so only minimal amounts of phosgene are distributed in the body. The very short half-life (0.026 seconds) in aqueous solutions precludes a significant retention of phosgene in the body. No information on the metabolism of phosgene has been reported. The hydrolytic products of phosgene, i.e. hydrochloric acid and carbon dioxide, are disposed of by the body through normal physiological processes (Manogue & Pigford, 1960; Thienes & Haley, 1972). 6.2 Reaction with body components Apart from the formation of hydrochloric acid on contact, Cessi et al. (1966) showed marked acylation of in vitro poly-L-lysine and human albumin by phosgene. The reaction of phosgene with cysteine yields 2-oxothiazolidine-4-carboxylic acid (Mansuy et al., 1977). The same product is formed when chloroform (Pohl et al., 1977) or carbon tetrachloride (Shah et al., 1979) is incubated with hepatic microsomes. 7. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS 7.1 Single and short-term inhalation exposures For some end-points (e.g., death, lung damage), the effects of phosgene exposure are dependent upon both the concentration and duration of exposure; considered as a product of CT=K as stated in Haber's law (the product of the concentration and time of exposure required to produce a specific physiological effect is a constant). Early workers validated this relationship using death as the physiological end-point following acute and short-term exposures. The validity of this concept for phosgene was tested in cats (Flury, 1921; Flury & Zernick, 1931). Twenty cats were exposed to phosgene at levels between 5 and 500 mg/m3 for periods of time between 0.5 and 120 min (CT values varied from 37.5 to 562 ppm-min). A plot of K (death or survival) against T (abscissa) and C (ordinate) resulted in an hyperbolic plot with marked deviations at both high and low concentrations (Long & Hatch (1961). Similar results were obtained in rats when the physiological effect was impaired gas exchange (Rinehart & Hatch, 1964). Based on reviews of available information (Coman et al., 1947; Atherley, 1985) it was concluded that, for phosgene, effects associated with the product of CT were reasonable constant only within the middle range of concentrations (i.e., between 4 and 800 mg/m3), and for exposure times that negated the effect of an animal holding its breath. Under these conditions and for these effects, it was considered appropriate to express the actual dose of phosgene, assuming equivalent respiratory volume, as CT. The CT relationship probably does not apply to potential effects resulting from long-term exposure to low levels of phosgene. Single and short-term exposures are described together because of the similar biological responses observed. Most of the numerous animals studied are summarized elsewhere (US EPA, 1986) and representative examples are shown (Table 3, Table 4). In inhalation studies the lung is the primary target organ in all species, and the characteristic pathological feature is the delayed clinical manifestation of pulmonary oedema, which is dose dependent. Other mucous membranes such as the eye can also be affected. Underhill (1919, 1920) exposed dogs for 30 min to phosgene concentrations between 176 and 480 mg/m3. At the lower concentrations he reported that phosgene exposures resulted in pathological lesions in the terminal bronchioles and alveoli, typical for a pulmonary irritant. However, at the higher exposure levels phosgene resulted in oedema leading to interference with gas exchange, cyanosis and eventually death. Table 3. Effects of phosgene after single exposure by inhalation Speciesa Exposure Effects Reference C x T C T (mg/m3-min) (mg/m3) (min) Rat 100 0.4 250 Widening of pulmonary intestices Diller et al. (1985) Rat 144 144 0.4-380 Reduced pulmonary bacterial Yang et al. (1995) clearance Cat 150 10 15 Slight illness Flury (1921) Mice, rats, 192 0.8 240 Increase in levels of lavage fluid Hatch et al. hamsters protein (1986) Rat 200 0.24 500 Increase in protein levels in Diller et al. (1985) 20 10 pulmonary lavage fluid Rat 200 20 10 Initiation of pulmonary oedema Diller et al. (1985) Rats (male) 240 1 240 Increase in levels of lavage fluid Currie et al. protein. Increase in the percentage (1987a) of polymorpho-nuclear leukocytes (PMN) Table 3 (contd). Speciesa Exposure Effects Reference C x T C T (mg/m3-min) (mg/m3) (min) Cat 440 44 10 L(CT)minimum Flury & Zernick (1931) Cat 450 10 45 L(CT)mimimum Flury & Zernick (1931) Guinea-pigs, 480 2.0 240 Increase in levels of lavage fluid Hatch et al. rabbits protein (1986) Rat 480 2 240 Increase of wet and dry lung weight Currie et al. (1987a) Rat 480 2 240 Decrease in pulmonary natural killer Burleson & Keys activity (NK) (1989) Cat 660 44 15 L(CT)100 Flury (1921) Cat 720 12 60 L(CT)100 Flury (1921) Mouse 900 60 15 L(CT)50 Cameron & Foss (1941) Table 3 (contd). Speciesa Exposure Effects Reference C x T C T (mg/m3-min) (mg/m3) (min) Monkey 1000 1000 1 L(CT)50 Diller & Zante (1982) Rat 1200 16 75 L(CT)50 Rinehart & Hatch (1964) Monkey 1320 440 3 L(CT)100 Winternitz et al. (1920) Dog 1800 180 10 L(CT)50 Diller & Zante (1982) Guinea-Pig 1920 128 15 L(CT)50 Underhill (1920) Rat 4000 400 10 Ultrastructural changes in the Pawlowski & bronchoalveolar region of lungs; Frosolono (1977) cellular disruption and necrosis Guinea-pig 6160 308 20 L(CT)100 Ong (1972) Dog 8808 2936 3 L(CT)99 Coman et al. (1947) Table 3 (contd). Speciesa Exposure Effects Reference C x T C T (mg/m3-min) (mg/m3) (min) Sheep 13 300 1330 10 L(CT)50 Keeler et al. (1990) Rabbit 21 140 604 35 L(CT)99 Coman et al. (1947) a In most cases the sex of the animals was not specified Necropsy of dogs that died shortly after single exposure to phosgene showed frothy material around the mouth, engorgement of the visceral vasculature (shock-like syndrome), and heavy wet congested lungs (Winternitz et al., 1920). Microscopically, the lungs were characterized by congestion and severe oedema. Proteinaceous fluid, strands of fibrin, and leukocytes filled the alveoli. In dogs that died 4 or more days after dosing, pulmonary infection (inflammation) was the primary cause of death. Oedema, congestion and emphysema of lesser severity were still present but there was also evidence of an attempt to repair tissue. In dogs that died or were killed later (11 to 129 days), necropsy revealed varying degrees of lung collapse and emphysema suggesting obliterative bronchiolitis. The epithelium of the larger airways (trachea and bronchi) did not show evidence of damage. The authors stated that the pathology of phosgene exposure was similar in the goat, dog, monkey, rabbit, guinea-pig, rat and mouse (Winternitz et al., 1920). Concurrent studies in a different laboratory confirmed the above results (Meek & Eyster, 1920). These authors documented a well-marked succession of events after exposure of dogs for 30 min to phosgene levels of 320-400 mg/m3. In the initial stage of exposure there is direct damage to the epithelial cells lining the pulmonary airways, with the distal ones showing the most damage. The cells are killed (necrosis) and sloughed. This is immediately followed by effusion of fluid into the affected airways (oedema). There is some damage to erythrocytes in pulmonary capillaries, which aggregate, thus causing occlusion. Gaseous exchange is interfered with, and death is the result of hypoxia/anoxia. Other authors (Cameron & Courtice, 1946) have also shown that pulmonary oedema is the primary cause of death in several species after acute phosgene poisoning (440 mg/m3). The area of lung affected appears to depend on the level of exposure. Gross et al. (1965) postulated that at lower levels the alveolar bronchioles and alveoli are the primary target tissues. At higher levels more proximal respiratory tissues are at risk of developing lesions. The relationship between the primary target site in the lung and dose of phosgene was confirmed in rats (Diller et al., 1985). Changes within the blood-air barrier (pulmonary oedema) were noted at phosgene levels of 20 mg/m3 (5 ppm) or more and at durations of exposure of 10 min or longer (50 ppm-min). The lowest dose of phosgene producing an increase in protein levels in pulmonary lavage fluid was also 200 mg/m3 min (50 ppm-min), and that for the production of widening within the pulmonary interstices was 100 mg/m3 min (25 ppm-min). However, there was no apparent threshold of phosgene concentration for these two parameters. Concentrations of phosgene studied were 0.4 to 20 mg/m3 (0.1 to 5 ppm). Changes noted at low concentrations (0.4 to 10 mg/m3; 0.1 to 2.5 ppm) were primarily located at the transition from terminal bronchioles to the alveolar ducts, while at higher concentrations (20 mg/m3, 5 ppm) damage to the alveolar pneumocytes (type 1) was reported (Diller et al., 1985). The earliest ultrastructural change observed in the bronchoalveolar region of lungs of rats exposed to 400 mg/m3 (100 ppm) for 10 min was characterized by vesiculation of bronchiolar epithelium immediately after exposure (Pawlowski & Frosolono, 1977). This was followed, 30 min after the exposure, by extracellular accumulation of serous fluid in interstitial spaces and alveoli. The final events were cellular disruption and necrosis. The extent of the long-term effects after acute exposure appears to depend on the severity of the initial pathology (Coman et al., 1947; Diller, 1985b). The relative sensitivity of female mice and male hamsters, rabbits, guinea-pigs and rats to 4-h phosgene exposures at concentrations of 0.4, 0.8, 2 and 4 mg/m3 (0.1, 0.2, 0.5 and 1 ppm) was studied by Hatch et al. (1986). As an indicator of phosgene- induced pulmonary oedema, levels of lavage fluid protein (LFP) were measured 18-20 h after exposure. Groups of seven or eight animals were examined at each exposure level. Phosgene-induced changes in LFP levels in mice, hamsters and rats occurred at phosgene levels of 0.8 mg/m3 (about 190 mg/m3 min) and above, whereas the minimal effective dose in guinea-pigs and rabbits was 2 mg/m3 (about 480 mg/m3-min). Rats were exposed 4 h/day, 5 days/week for 17 exposures at a level of 0.5 or 1 mg/m3 (0.125 or 0.25 ppm) and killed on days 3, 7, 10, 13 or 17 or on days 2 or 20 after exposure. After day 7 the lung wet weights were increased by 20-25% (p < 0.05 in the high-level group). In the low-level group the lung wet weights increased with exposure time but were significantly increased only at day 17. These changes were paralleled by an increased activity of the pulmonary glucose-6-phosphate dehydrogenase. The non-protein sulfhydryl content in the lungs was elevated throughout exposure in both groups. All deviations were reversible after exposure ceased. At day 17 in the high-level group a moderate multifocal accumulation of mononuclear cells in the walls of the terminal bronchioli and their adjacent alveoli was observed. A minimal amount of type II alveolar cell hyperplasia was also found in this region. Macrophages with vacuolated cytoplasm were seen in the lumens of some alveolar ducts and alveoli. The lesions in the lungs of the low-dose animals were described as being minimal (Franch & Hatch, 1986). A no-observed- effect-level could not be demonstrated in this study. The effects of low-level acute exposure to phosgene in male rats was also studied by Currie et al. (1987a), who exposed groups of adult animals (250-300 g) for 4 h to 0.5 to 4 mg/m3 (0.125 to 1 ppm). Dose-related changes in body weight, wet and dry lung weights, LFP, total cell counts, and cell differentials were measured at the conclusion of the exposure and 3 days after exposure, at least 10 animals being sacrificed each time. A dose-response relationship for the measured parameters was noted. Both wet and dry lung weights increased after exposure to 120 and 240 ppm-min, and an increase in LFP was noted at > 60 ppm-min. The most sensitive cellular indicator of phosgene pulmonary damage was the increase in the percentage of polymorphonuclear leukocytes (PMN); there was a significant increase at 60 ppm-min. Both PMN and LFP can be used as sensitive indicators of pulmonary damage by phosgene after acute exposure. All parameters returned to control levels 3 days after exposure, indicating that the pulmonary damage within the dose-range studied was reversible. In Table 3, effects of inhalation exposure to phosgene have been summarized according to the degree of exposure, expressed as mg/m3-min. Pulmonary bacterial clearance appears to be the most sensitive end-point for acute phosgene toxicity in rats (about 100 mg/m3-min). The lowest dose of phosgene that produced an increase in protein levels in pulmonary lavage fluid and changes in the blood-air barrier (pulmonary oedema) was 100 to 200 mg/m3-min. This effect can be considered as the early critical effect of acute exposure to phosgene. Data presented in Table 4 suggest that evaluation of exposure according to Haber's law can be applied as the basis for constructing dose-effect relationships only in the case of acute relatively high exposures. Studies of pulmonary physiology in animals mirror the pathological observations (Gibbon et al., 1948; Boyd & Perry, 1960; Long & Hatch, 1961; Rhinehart & Hatch, 1964). Progressive loss of capacity for gas exchange is the initial and critical event. The respiration rate is increased but there is increased resistance and poor ventilation. 7.2 Skin and eye irritation; sensitization Very little information on this subject is available. Skin irritation is possible if concentrations are high enough, but the hazard is minimal compared to the severe lung damage that can be produced by much longer levels (Diller, 1985a; Borak, 1991). No studies on sensitization have been reported. Eye irritation and corneal oedema have been reported in dogs exposed to lethal concentrations of phosgene (Winternitz et al., 1920). Table 4. Toxicity of phosgene after repeated exposure by inhalation Speciesa Exposure Effects Reference Rat 0.4 mg/m3; 6 h/day, 5 days/week, Pulmonary bacterial clearance inhibited Selegrade et al. 4-12 weeks (1989) Rat 0.5-1 mg/m3 4 h/day 5 days/week, 17 Lung wet weight increase (20-25%); GPDb Franch & Hatch (1986) exposures activity increase; alveolar cell hyperplasic; macrophages with vacuolated cytoplasm Guinea-pig 0.8 mg/m3 for 300 min daily, 5 days Pulmonary oedema in 70% of animals Cameron et al. (1942) Cat 0.8 mg/m3 for 300 min daily, 5 days Pulmonary oedema in 70% of animals Cameron et al. (1942) Mouse 4 mg/m3 for 300 min daily, 5 days L(CT)90 Cameron & Foss (1941) Rat 4 mg/m3 for 300 min daily, 5 days Pulmonary oedema in 80% of animals Cameron & Foss (1941) Rabbit 4 mg/m3 for 300 min daily, 5 days L(CT)20 Cameron & Foss (1941) Dog 96-160 mg/m3 for 30 min Up to 20-fold increase in airway Rossing (1964) 1-3 times per week, resistance 12 weeks a Sex not specified b GPD= glucose-6-phosphate dehydrogene 7.3 Long-term exposure Long-term exposure studies of phosgene have not been conducted. However, there have been a limited number of studies on the effects of phosgene following repeated exposures over periods of time (dosing 1 to 3 times per week for up to 12 weeks) (Clay & Rossing, 1964; Rossing, 1964). Adult mongrel dogs (sex not identified) were exposed to phosgene at concentrations between 96 and 160 mg/m3 for 30 min, 1 to 3 times per week. Rossing (1964) exposed 14 animals 3 times weekly until increased airway resistance was noted, and then the frequency of exposure was decreased to 1 or 2 times weekly for 12 weeks. Seven animals died during the first 3 weeks of exposure and only three animals survived the full 12 weeks; two of which were maintained for 12 weeks with further exposure. The lungs of all animals were examined within 48 h after-exposure. After the initial inflammatory reaction, the ensuing lesion consisted of chronic bronchiolitis and emphysema that persisted for the duration of the exposure period. After cessation of exposure, elastance dropped rapidly to normal, but airway resistance was still elevated 11 weeks after exposure.In a similar experiment, Clay & Rossing (1964) studied the development of pulmonary emphysema in adult mongrel dogs after exposure to phosgene at concentrations between 96 and 160 mg/m3 for 30 min at a rate of 1 to 3 exposures per week. Group size varied between four and seven animals. The number of exposures varied between 1 and 25, and the dogs were killed either immediately or up to 2 weeks after exposure. However, in view of the low number of animals used, the experimental design and the lack of reported dose-response information, these data are difficult to use in assessing quantitatively the long-term risk to humans from phosgene exposure. 7.4 Reproductive and developmental toxicity No data were found on reproductive or developmental effects of phosgene in experimental animals. 7.5 Mutagenicity and related end-points No studies on the mutagenicity of phosgene have been reported. 7.6 Carcinogenicity No adequate studies are available for the assessment of the carcinogenicity of phosgene. In a review of the potential carcinogenicity of 266 substances found in various workplaces, data from one study involved 20 guinea-pigs and 20 rats that were exposed by inhalation to phosgene for 24 and 18 months, respectively. No pulmonary neoplasms were observed (Schepers, 1971), but information on dosing regimen, sex or strain of animals was lacking. 7.7 Immunotoxicity In one study, the immunotoxic effects in Fischer-344 male rats of a single 4-h exposure to 0, 0.4, 2.0 or 4 mg phosgene/m3 were reported (Burleson & Keys, 1989). As a measure of pulmonary immunocompetence the authors measured the natural killer (NK) activity of pulmonary cells on the day after phosgene exposures. At exposures of 2 and 4 mg/m3 there was a significant decrease in pulmonary NK activity, which was considered by the authors to be an indication of decreased immunocompetence. At 4 mg/m3 this decrease was still significant 4 days after exposure. A significant decrease was also noted at 2 mg/m3 one day after exposure, but no effect was seen at 0.4 mg/m3. Phosgene did not affect NK activity in blood lymphocytes, but NK activity in the splenic cells was decreased 1 day after exposure to 4 mg/m3. Effects on NK activity in lymphocytes and splenic cells at other phosgene doses and days post-treatment were not reported. Decreased immunocompetence in rats resulting from a 4-h exposure to phosgene was reported by Ehrlich & Burleson (1991). After male Fischer-344 rats (8-10 weeks old) were exposed to phosgene at 4 mg/m3 for 4 h, the animals were infected with a rat-adapted influenza virus and the virus titre measured at 2 h and 1, 2, 3, 4, 5 and 7 days post-infection. The virus titre was measured in three replicate experiments using three rats per group. Following an initial decrease in the viral titre at 2 h after infection, the virus titre increased by a factor of 10 on the day after infection and remained significantly higher than in controls up to 4 days after infection. The virus was cleared below detectable levels after 5 days post-infection. Bacterial clearance was assessed in male Fisher-344 rats exposed to 0, 0.4 or 0.8 mg/m3 (0.1 or 0.2 ppm) phosgene for 6 h (Yang et al., 1995). Immediately after exposure to phosgene the animals were infected with Streptococcus zooepidemicus, and the number of bacteria in the pulmonary lavage fluid was assessed up to 72 h later. Pulmonary bacterial clearance was significantly reduced (p <0.05) following exposure to 0.4 mg/m3 (0.1 ppm) phosgene (LOEL = 0.1 ppm). Based on an analysis of other immunological parameters (e.g., pulmonary NK activity and pulmonary macrophage function), the authors indicated that bacterial clearance appeared to be the most sensitive end-point for acute phosgene toxicity in rats. CD-1 mice were exposed to phosgene concentrations of 0.04 to 0.4 mg/m3 (0.01 to 0.1 ppm) for 4 h and infected with S. zoo- epidimicus or inoculated with B16/BL6-melanoma tumour cells. At and above 0.1 mg/m3 (0.025 ppm), mortality due to the infection with S. zooepidimicus and the number of B16/BL6 melanoma tumours in the lungs were both elevated. An 8-h exposure to 0.04 mg/m3 increased the mortality due to S. zooepidimicus but not the number of B16/BL6 melanoma tumours (Selgrade et al., 1989). F-344 rats were exposed to phosgene concentrations of 0.2 to 4 mg/m3 (0.05 to 1 ppm) and their lungs lavaged 0, 4, 20 or 44 h later. At and above 0.4 mg/m3 the concentrations of prostaglandin E2 as well as of leukotrienes B4, C4, D4 and E4 were decreased by 29 to 69%. The eicosanoid concentrations after exposure to 0.4 and 1 mg/m3 returned to normal 44 h later. After exposure to 0.4 or 4 mg/m3, but not to 0.2 mg/m3, the number of alveolar macrophages was decreased, whereas the number of neutrophils was increased at 44 h after exposure to 0.4 mg/m3, but not to 4 mg/m3 (Madden et al., 1991). Pulmonary effects have also been observed in male Fisher-344 rats exposed for a longer term to phosgene (Selgrade et al., 1995). Groups of animals were exposed to 0, 0.4 or 0.8 mg/m3 (0, 0.1 or 0.2 ppm) for 6 h/day, 5 days/week for 4 or 12 weeks, or to 2 mg/m3 (0.5 ppm) for 6 h/day, 2 days/week for 4 or 12 weeks. When assessed immediately after 4 or 12 weeks of exposure, pulmonary bacterial clearance was inhibited following exposure to 0.4 mg/m3 (0.1 ppm) phosgene (LOEL = 0.1 ppm). This effect appeared reversible, since pulmonary bacterial clearance was unchanged when assessed 4 weeks after a 12-week exposure period. These subchronic effects on pulmonary bacterial clearance were similar to those observed previously, following acute exposure to phosgene (Yang et al., 1995). In animals administered the same dose of phosgene, pulmonary bacterial clearance was more severely affected in animals exposed to the higher concentration of this substance (i.e., 2 mg/m3 (0.5 ppm), 6 h/day, 2 days/week, compared to 0.8 mg/m3 (0.2 ppm) 6 h/day, 5 days/week). A significant reduction in pulmonary NK activity was observed following exposure to 2 mg/m3 (0.5 ppm). 7.8 Mechanism of toxicity Although the exact mechanism of phosgene toxicity remains unknown, it seems likely that the original hypothesis of Winternitz et al. (1920), suggesting that hydrochloric acid was the causal agent for the pulmonary effects noted, is incorrect. Current data indicate that the effects from phosgene exposure result from the acylation of tissue components, although the production of HCl may play a minor role, particularly at high levels of exposure (Diller, 1985a). Nash & Pattle (1971) studied the chemical reactivity of phosgene when bubbled through aqueous solutions at various pH values, some containing amines, phenoxide ions or sulfite. From these data it was concluded that molecular phosgene could penetrate all layers of the blood-air barrier, causing the observed pathology by reacting with chemical groups in the cells. It was shown mathematically that insufficient HCl to produce the observed effects could be generated under physiological conditions and phosgene exposures as high as 100 mg/m3 (25 ppm). Early evidence that acylation of amino, hydroxyl and sulfhydryl groups was the major mechanism was reported by Potts et al. (1949). Rats and mice exposed to 0.5 mg ketene/litre for 1.5 min showed clinical signs and pathological lesions identical to those cause by phosgene. Ketene is a known acrylating agent that does not break down to a strong acid. The effects on pulmonary ultrastructure and enzyme activities in adult rats from exposure to phosgene for 10 min at 400 mg/m3 (100 ppm) were studied by Pawlowski & Frosolono (1977) and Frosolono & Pawlowski (1977). Homogenates of the combined lungs from six to eight rats were assayed for several enzyme activities in duplicate immediately after exposure and at 30 and 60 min post-exposure. A decrease in the enzymatic activity of 10-80% was noted at all time periods for p-nitrophenyl phosphatase, cytochrome C oxidase, ATPase and lactic dehydrogenase (Frosolono & Pawlowski 1977). Using the same protocol Pawlowski & Frosolono (1977) examined the cascade of ultrastructural changes in the terminal bronchiolar epithelium after exposure. An immediate vesiculation of cells was followed by septal extracellular oedema and, finally intracellular oedema, cell disruption and necrosis. The authors suggested that the biochemical changes preceded major ultrastructural changes in the alveolar region. Currie et al. (1985) studied the effects on energy metabolism of exposure to 4 mg/m3 (1 ppm) for 4 h (CT = 960 mg/m3-min) in rats. An attempt was made to correlate the onset of pulmonary oedema with alterations in energy metabolism. At the exposures studied, there was a significant reduction in the respiratory control index, which coincided with the highest level of percentage water in the lung. In addition, a decrease in ATP concentration was noted. It was concluded that reductions in ATP levels and Na-K-ATPase activity play a major role in damage to the lung after phosgene exposure and prior to the onset of oedema. Studies by Currie et al. (1987b) have confirmed these findings at lower doses. Rats were exposed for 4 h to 48, 120, 240, 480 or 960 mg/m3-min (12, 30, 60, 120 or 240 ppm-min). Decreased ATP levels were noted prior to the onset of oedema at doses as low as 48 mg/m3-min (12 ppm-min) after exposure for 4 h. Further studies by Frosolono & Currie (1985), using the same exposure regimen as Currie et al. (1985) (i.e., 960 mg/m3-min), indicated that phosgene may alter the level of pulmonary surfactant thus altering the homeostatic mechanism for fluid balance in the lung. Jaskot et al. (1991) studied the effect of inhaled phosgene on lung anti-oxidant systems in Fischer-344 male rats. Levels of 0, 0.4, 1, 2 and 4 mg/m3 were administered for 4 h and a satellite group received 1 mg/m3 for 8 h. Changes in glutathione (GSH) and anti-oxidant associated enzymes (GSH peroxidase, GSH reductase, glucose-6-phosphate dehydrogenase and superoxide dismutase) were measured 0, 1, 2, 3 and 7 days post-exposure in groups of 12 animals per dose. At all dose levels significant increases were noted for one or more components of the anti-oxidant system studied. Peaking at 2 to 3 days post-exposure, the changes noted were similar to those observed after exposure to the pulmonary irritants ozone and nitrogen dioxide. The role of arachidonic acid metabolites in the pathogenesis of phosgene-induced lung injury (oedema and vascular permeability) was studied in rabbits (Guo et al., 1990). Animals (four to six per group) were exposed to 6000 mg/m3-min (1500 ppm-min) of phosgene and killed 30 min after-exposure. The effects were compared to those of a control group of eight animals. Lungs were perfused for 90 min and cyclooxygenase- and lipoxygenase-generated metabolites of arachidonic acid were measured. Phosgene exposure did not enhance the cyclooxygenase metabolism of arachidonic acid but did result in a 10-fold increase in lipoxygenase metabolites (leukotriene). A marked decrease in the gain in lung weight after phosgene exposure was reported when the perfused lung was pretreated with leukotriene receptor blockers. The results suggest that lipoxygenase metabolites of arachidonic acid contribute to the phosgene-induced pulmonary damage, but the mechanism by which phosgene stimulates the metabolism of arachidonic acid is still unknown. Evidence that the non-cardiogenic pulmonary oedema and mortality resulting from phosgene inhalation was the result of an influx of neutrophils into the lung was provided by Ghio et al. (1991). After exposure of rats to 2 mg phosgene/m3 (0.5 ppm) for 60 min, significant increases in the percentage of neutrophils and concentrations of protein and thiobarbitunic acid reactive products in bronchoalveolar lavage fluid were noted. These increases were significantly less after treatment prior to exposure with: cyclophosphamide to deplete the leukocytes; inhibition of the production of the chemotaxis leukotriene B4, which directs the influx of neutrophils into the lung; or treatment with colchicine, which decreases leukocyte migration. These treatments in mice exposed to 8 mg phosgene/m3 (2.0 ppm) for 90 min resulted in decreased mortality. Colchicine reduced neutrophil influx, lung injury and mortality in mice even when administered 30 min after exposure. Preliminary evidence that F-actin in lung cells may be a target of phosgene was reported by Werrlein et al. (1994). In cultured ovine pulmonary artery endothelial cells and rat airway epithelial cells exposed to phosgene there was a dose-dependent decrease in the F-actin content and organization. Exposure of sheep to 0.15 L(CT)50 (96 mg/m3 for 20 min) led to a decrease in the F-actin concentration of endothelial cells. Exposure of sheep to 0.83 L(CT)50 (548 mg/m3 for 20 min) disrupted basal lamina and produced paracellular leakage paths in the cultured cells. If they occur in vivo, these effects of phosgene on F-actin may contribute to the decreased barrier function and increased permeability of vascular tissues. 8. EFFECTS ON HUMANS 8.1 General population and occupational exposure The information on the effects of high-level, short-term phosgene exposure in humans is derived from wartime experiences as well as from industrial accidents. General population and occupational exposures to high levels of phosgene will be discussed together, since the immediate effects and outcome of such exposures are identical in both populations. As with animal experiments (see section 7.1), the acute effects in humans are reported as a result of a combination of exposure level and time of exposure (mg/m3-min). The exposure levels at which perception of the odour is possible compared to those that cause varying degrees of toxicity and death in humans are presented in Table 5. In "trained subject" the lowest level at which the odour (like mouldy hay) is perceived is 1.6-2 mg/m3 (NIOSH, 1976), but at such levels workers may not detect the odour due to olfactory fatigue (Proctor & Hughes, 1991). Under normal conditions the odour is recognized only at levels greater than 6 mg/m3 (1.5 ppm). Signs of irritation of mucous membranes are observed at > 12 mg/m3 (3 ppm), early lung damage at > 120 mg/m3-min (>30 ppm-min), and death (L(CT)50) at approximately 2000 mg/m3-min (approximately 500 ppm-min) (Diller & Zante, 1982; Diller, 1985a). As shown in Table 5, concentrations of phosgene vapour > 2 mg/m3 (3 ppm) will result in irritation of the eyes and nose. Such concentrations in contact with moist skin will also lead to irritation and erythema (Borak, 1991), but there is no evidence that they would result in serious skin injury. At 12 mg/m3 (3 ppm) the only effect reported on the human eye was inflammation (conjunctival hyperaemia) (Grant & Schumann, 1993). Liquid phosgene splashed in the eye, however, caused complete corneal opacification, conjunctival adhesions and perforation in one victim (Grant & Schumann, 1993). Although skin contact can result in severe burns, no reports of such cases are available. Table 5. Correlation of phosgene dose and effects in humansa Effects Dose levelb Perception of odour 1.6 mg/m3 0.4 ppm Recognition of odour 6 mg/m3 1.5 ppm Irritation of eyes, nose, and throat 12 mg/m3 3 ppm Beginning lung damage >120 mg/m3-minc > 30 ppm-min Pulmonary oedema >600 mg/m3-minc > 150 ppm-min L(CT)1 approx 1200 mg/m3-minc approx 300 ppm-min L(CT)50 approx 2000 mg/m3-minc approx 500 ppm-min L(CT)100 approx 5200 mg/m3-minc approx 1300 ppm-min a From: Diller (1985a) b A conversion factor of 4 was used to calculate mg/m3 from the ppm value used by author. c These values should be considered in relation to Haber's Law (see section 7.1). With respect to pulmonary damage, three distinct clinicopathological phases (initial reflex syndrome, clinical latent phase and clinical oedema phase) have been reported in humans acutely exposed to phosgene levels of 120 mg/m3-min to 1200 mg/m3-min (30-300 ppm-min) (Diller & Zante, 1982; Diller, 1985a). During and immediately after exposure the individual experiences pain in the eyes and throat (an irritating or burning sensation) and tightness in the chest, which may be accompanied by shortness of breath and coughing. This is followed by a latent phase, which is often asymptomatic. Depending on total dose this period may last from 1 to 24 h. The oedema phase is manifested when enough lung is affected to become clinically apparent, i.e. shortness of breath, productive cough, and/or expectoration of large amounts of frothy and possibly bloody sputum. If enough of the lung is involved the person may become cyanotic and enter into shock. If the exposure is in the lethal range, the early phases may be truncated, and the latent phase may be very short or non-existent. It has been reported that radiographs taken immediately after exposure can be used to predict the severity of ensuing pulmonary oedema (Ardran, 1964). The author stated that an increase in lung volume following expiration is highly predictive for the future development of oedema. 8.2 Case reports - individual accidents The most definitive data on both the short- and long-term effects of acute phosgene exposure in humans is found in case reports of industrial accidents. Such accidents may also pose a potential hazard to adjacent communities. In Hamburg, Germany, an industrial storage tank released 11 tonnes of phosgene into the atmosphere in 1928 (Hegler, 1928). The atmospheric conditions were conducive to the slow spread of the gas outside the plant. No exposure levels were reported. During a period of 5 days, over 300 people became ill, of whom 10 died. The initial symptoms were severe irritation of the eyes and throat, coughing, tightness of the chest, nausea and vomiting. Autopsies of some of the victims revealed typical pulmonary lesions and nonspecific lesions in other organs that were attributable to local hypoxia (Wohwill, 1928). The author also felt that some degenerative lesions in the brain and spinal cord were due directly to phosgene, but this has not been confirmed in subsequent studies. The only reference to the long-term effects in this population was that there was no apparent damage to health 2 months after the accident. In November 1966, phosgene was accidentally released from a factory in Japan; 382 people were poisoned and 12 were hospitalized (Sakakibara et al., 1967). Signs and symptoms observed in the 12 patients on admission were headache (9), nausea (9), cough (8), dyspnoea (7), fatigue (7), pharyngeal pain (5), chest tightness (5), chest pain (5), and fever (3). Lacrimation and redness of the eyes were only observed in one patient. Seven patients showed evidence of pulmonary oedema as revealed by chest X-rays 48 h after the exposure. These findings indicate that pulmonary oedema may develop even 48 h after exposure without initial symptoms of eye or nose irritation. Other industrial accidents that have been reported usually involved only a few people and no details of exposure levels were given. The clinicopathological syndrome was similar in all of these reports (Everett & Overholt, 1968; Stavrakis, 1971; Regan, 1985). The predominant finding during and immediately following exposure was irritation of mucous membranes. Victims described intense pain in the eyes with profuse lacrimation. At the same time there was a burning sensation in the throat and tightness of the chest. Coughing ensued, often of a very severe nature. Victims sometimes did not show any other symptoms. However, more common was the subsequent development of pulmonary oedema, which, if sufficiently severe, resulted in death due to interference with gas exchange. In none of the case reports of direct phosgene exposure was any data on the actual levels of phosgene given. Several case studies of phosgene poisoning have been reported where the patient was not working directly with phosgene. Such reports include those of Seidelin (1961) on carbon tetrachloride used to extinguish a fire, those of Glass et al. (1971) and Sjogren et al. (1991) on the decomposition of trichlorethylene during welding and those of Gerritsen & Buschmann (1960) and Snyder et al. (1992) reporting possible phosgene poisoning due to the thermal degradation of methylene chloride used to remove paint. All of these chemicals are known to be degraded thermally to phosgene. Furthermore, the progression of effects (clinical latent phase) after exposure, the development of dyspnoea, chest discomfort and pulmonary oedema in all subjects was typical of phosgene poisoning reported in case studies of direct phosgene exposure. There are relatively few reports on the long-term sequelae of an acute exposure. In a review of this subject, Diller (1985a,b) found that the vast majority of survivors of acute exposure have a good prognosis. However, some of those exposed to high levels of phosgene showed chronic symptoms such as shortness of breath and reduced physical capacity, which persisted, in some cases, for the rest of their lives. However, the severity and duration of such effects was also related to subsequent smoking habits. Pre-existing pulmonary disease such as emphysema was exacerbated by phosgene exposure. While most published reports indicate that the respiratory tract is the primary target organ for phosgene poisoning, a few reports have indicated effects on other organs, especially the heart and brain (Diller, 1985a,b). Neurasthenia is the most common of these conditions associated with acute phosgene exposure. Others are an epilepsy-like syndrome, loss of speech, peripheral Raynaud-like syndrome and a type of paralysis characterized by disfunction of the peroneal nerve. A causal relationship between phosgene exposure and such effects has yet to be confirmed. It has been suggested by Diller (1985b) that such changes are more likely a result of anoxia from the pulmonary oedema rather than the direct action of phosgene. 8.3 Epidemiological studies Phosgene, isopropyl alcohol, aniline and caustic soda are raw materials used in a Russian plant for the manufacture of the herbicide, isopropylphenyl carbamate. Levina & Kurando (1967) found phosgene at levels of about 0.5 mg/m3 in 30% of all air samples. In 89 workers studied no mention was made of pulmonary problems. However, methaemoglobinaemia and anaemia were detected and attributed to exposures to aniline and the herbicide itself. At a phosgene factory in the USA the medical records of all workers exposed (326) and 6228 non-exposed workers were compared (NIOSH, 1976). Limited air sampling conducted during a 2-month period using the NBP method of analysis with 20-min sampling time (passive dosimetry Table 2), indicated an average exposure to phosgene of 0.01 mg/m3 (ND to 0.08 mg/m3). Out of 56 fixed-position samplers (2-h or 20-min collection) 51 showed phosgene levels of up to 0.52 mg/m3 and five samples showed levels greater than 0.55 mg/m3 (off the scale). Deaths attributable to respiratory disease and pulmonary function (defined as "lung problems") were compared. No chronic lung problems associated with working at these phosgene levels were reported, nor was there any increased mortality from respiratory disease in the exposed workers. Polednak (1980) described a study of a cross-section of workers exposed to phosgene at a uranium processing plant between 1943 and 1947. The study contained one group of 699 white male workers exposed routinely to low (but undetermined) levels of phosgene with daily episodes (4 or 5 daily) of exposures to levels above 4 mg/m3. A second group of 106 white males involved in accidents resulting in acute exposures to phosgene at levels estimated by the authors to be greater than 200 mg/m3-min. This estimate was based on initial symptoms reported and clinical data obtained immediately after exposure. All workers reported detecting the odour of phosgene, 82 reported chest pain and dyspnoea, 25 showed x-ray and clinical evidence of pneumonitis and 1 worker died 24 h after the exposure from pulmonary oedema (based on clinical symptoms). The control group contained 9352 non-exposed workers at the same facility. Those workers employed for 2 days or more in departments where phosgene exposure was possible were considered to be in the exposed group. Mortality data was determined by examination of the Social Security Administration records and coding the cause of death using the Eighth Revision of the International Classification of Diseases. As of 1974 there was no evidence of excess mortality from diseases of the respiratory system in the group of 699 male workers (about 30 years after exposure). In fact standardized mortality ratios (SMR) for death from all causes were essentially the same in both the exposed and control groups. The Task Group noted that possible simultaneous exposure to ionizing radiation was not taken into account. In 1974, 30 deaths had occurred in the 106 workers exposed to high levels of phosgene (SMR = 113). No deaths from lung cancer were noted but three deaths (1.37 expected) were due to respiratory diseases. One worker in this group died from pulmonary oedema 24 h after exposure. A follow-up of the workers from the cohort studied by Polednak (1980) was made by Polednak & Hollis (1985). Similar trends to those reported earlier were noted 35 years after exposure. Of the 694 workers chronically exposed, there were 14 deaths from diseases of the respiratory tract (13.1 expected) (SMR = 107; 59-180 95% CI). In 1974, the SMR for lung cancer within the 699 chronically exposed workers was 127 (95%, CI 66-220) and in 1979 it was 122 (72-193, 95% CI). The slightly elevated SMR values were not significantly higher than controls. The SMR for death from all causes was 97 (85-111 95% CI) in the exposed workers and 101 (98-104 95% CI) in controls. In the high- exposure group there were 41 deaths from all causes compared to 33.9 expected (SMR = 121; 86-165 95% CI). Five deaths were coded to diseases of the respiratory tract (SMR = 266; 86-622 95% CI). In two of these cases, bronchitis due to phosgene poisoning had been reported in 1945 during clinical examination after exposure. There have been no epidemiological or case reports linking the development of reproductive or teratogenic effects in humans to acute and/or chronic phosgene exposures. 9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD No information concerning the effects of phosgene in the laboratory and field has been reported. 10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT 10.1 Evaluation of human health risks 10.1.1 Exposure Exposure to phosgene is primarily by inhalation. There are three exposure situations: chronic exposure of the general population to extremely low levels; chronic exposure in the workplace to very low levels; and accidental acute exposure to high levels. It is likely that the principle source of exposure to phosgene for the majority of the general population is through the photo-degradation and thermal degradation of chlorinated hydrocarbons, especially solvents and polymers (e.g., tri- and tetrachloroethylene and PVC). On the basis of limited data, average levels of phosgene in ambient air can be expected to vary between 80 and 130 ng/m3. Available data are inadequate to determine quantitatively the exposure to phosgene in the workplace. Those working simultaneously with flames (or thermal energy sources) and organochlorine solvents or PVC can be exposed to phosgene levels well above present threshold limit values (time-weighted average) of 0.4 mg/m3. Accidental release of phosgene during its manufacture, use or transport can lead to high levels of exposure for workers and for the general population in the vicinity of the accident. 10.1.2 Health effects Phosgene is a highly reactive chemical, hydrolysing to hydrochloric acid, and is capable of acrylating nucleophilic groups, such as amino, hydroxyl and sulfhydryl groups, in tissues. In all species studied, including humans, the major target organ is the lung. High concentrations can also cause skin and eye irritation. For health effects after acute exposure, Haber's Law, which states that the toxicological effect is due to the product of exposure (C) and time (T), holds between levels of 4 and 800 mg/m3 (1 and 200 ppm) using lung disease and death as toxicological end- points. This law does not, however, prevail for chronic exposure. The cascade of events after acute inhalation exposure in humans and experimental animals are similar. It occurs in a dose-related manner and results in pulmonary oedema and death in humans, which is dose-dependent at levels exceeding 120 mg/m3-min. Three distinct clinicopathological phases can be recognized: pain in the eyes and throat and tightness of the chest, often with shortness of breath, wheezing and coughing; a latent phase that is often asymptomatic and can last up to 24 h depending upon the concentration and duration of exposure; and the final phase of pulmonary oedema. 10.1.2.1 Evaluation of animal data The L(CT)50 and L(CT)100 values for single exposure vary widely among animal species (Table 3). In all species the characteristic pathological feature is the delayed clinical manifestation of pulmonary oedema, which is dose-dependent. The extent of the long-term chronic effects of acute exposure appears to depend on the severity of the initial pathology.Single exposure of rats for 4 h to between 0.5 and 4 mg/m3 resulted in a dose-related increase in lavage fluid protein (LFP) concentration and an increased percentage of polymorphonuclear leukocytes (PMN) in the alveoli. Changes in the LFP and PMN were the most sensitive parameters occurring at 240 mg/m3- min. These changes were reversible within 3 days after exposure. There have been no long-term exposure studies in animals, and studies in dogs exposed 1-3 times/week for 12 weeks are of limited value for risk assessment in view of inadequate study design and lack of dose- response. Available data in experimental animals are inadequate for the assessment of the potential reproductive, developmental, neurotoxic and carcinogenic effects resulting from phosgene exposures. Single 4-h exposures to 0.1 mg phosgene/m3 in mice have resulted in a demonstrable decrease in pulmonary host resistance to bacteria. Rats exposed to 2 or 4 mg/m3 for 4 h had decreased pulmonary cell natural killer (NK) activity, whereas no effect was seen at a level of 0.4 mg phosgene/m3 for 4 h. Increased infectivity by influenza virus was reported in rats exposed for 4 h to 4 mg/m3. Virus titres were not detectable 4 days after infection. Mortality was increased after exposure to S. zooepidemicus and inoculation of B16/BL6 pulmonary melanoma tumours in mice exposed to phosgene levels at or above 0.1 mg/m3. No effect was reported at a level of 0.04 mg/m3. Pulmonary bacterial clearance was reduced in rats exposed to 0.4 mg/m3 (0.1 ppm) phosgene for 6 h and to 0.4 mg/m3 (0.1 ppm) for 6 h/day, 5 days/week for 4 to 12 weeks. This effect was reversible following termination of exposure. 10.1.2.2 Evaluation of human data As a result of industrial accidents and occupational monitoring (levels and health status), it has been reported that some humans can only recognize the odour of phosgene at levels of about 6 mg/m3, making this an unacceptable parameter for early warning. After short-term exposure, throat and eye irritation occurs at a level of 12 mg/m3 and eye irritation is noted at 16 mg/m3. The risk of morbidity and mortality after acute exposure, is determined by the dose (CT), not solely by concentration. It has been calculated that doses below 100 mg/m3-min result in no effect, whereas pulmonary oedema results from doses above 600 mg/m3-min. It should be recognized, however, that death has been recorded at doses above 400 mg/m3-min, although with proper medical intervention death may be prevented. Exposures for several hours at or below the odour threshold (6 mg/m3) may result in severe tissue damage and death. A review of the health status of workers who have recovered from acute phosgene exposures has shown no adverse effects. However, full recovery may take several months. Available data on human health effects associated with chronic exposure to phosgene are extremely limited. Epidemiological studies of phosgene production workers and uranium workers reported no adverse effects on human health. However, these investigations are of limited value owing to the small numbers of exposed workers, lack of reliable quantitative information on exposure to phosgene, concomitant exposure to other substances, limited number of end-points examined and limited reporting of relevant information. Available data are therefore considered inadequate to assess the risk associated with long-term exposure to low levels of phosgene. 10.1.3 Guidance value Available data is considered inadequate to derive a meaningful health-based guidance value for exposure of the general population to phosgene. Information from epidemiological studies of occupationally exposed workers is insufficient to characterize quantitatively exposure-response relationships associated with potentially adverse health effects resulting from exposure to this substance. Appropriate studies in laboratory animals are lacking, and the available toxicological investigations do not provide relevant data upon which development of a credible guidance value for the long-term exposure of humans to phosgene can be based. Recent toxicological studies of rats subchronically exposed by inhalation to low levels of phosgene indicate that early pulmonary effects may occur at present TLV values. Thus, consideration by appropriate authorities should be given to re-evaluating current occupational exposure guidelines for this substance. 10.2 Evaluation of effects on the environment The levels of phosgene now found in the environment would not be expected to result in significant effects to aquatic or terrestrial biota. However, no data were found to substantiate or refute this hypothesis. Damage to plants and aquatic organisms, owing to the rapid release of hydrochloric acid, could occur in areas where accidental release of phosgene has occurred. 11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH 11.1 Conclusions a) Phosgene is an extremely reactive chemical with the potential to cause adverse effects in humans, the primary target organ being the respiratory system. b) Acute severe phosgene exposure primarily causes respiratory disease (pulmonary oedema) and may result in death. Survivors may recover completely provided they receive proper medical support. c) Present levels of exposure to phosgene in the general population are extremely low and do not pose a health risk in the short term. However, humans working with chlorinated solvents such as trichloroethane, tetrachloroethylene and methylene chloride or who are exposed to chlorinated hydrocarbon polymers (e.g., PVC) in contact with flames or other thermal energy sources can be exposed to levels of phosgene known to cause adverse effects in humans. This could apply to firemen, welders, painter or people working at home with the above-mentioned materials. d) Accidental industrial releases can cause health problems in workers and in the nearby community. e) Workers have been shown not be at risk in closed-system industrial facilities that manufacture or use phosgene and employ good industrial practice. f) No human or animal data are available on the effects of chronic low-level exposures to phosgene. g) No data are available concerning adverse effects on organisms in the environment. However, accidental release would be expected to give rise to adverse effects. 11.2 Recommendations for protection of human health a) Present occupational exposure limits for phosgene should be re-assessed. b) Data should be obtained on the release of phosgene by the incineration of chlorine-containing organic materials. c) International and national regulations regarding transport of phosgene should be followed in order to avoid accidental releases. d) Analytical methods capable of monitoring whole shift individual exposure (e.g., paper tape monitors) should be used routinely in the workplace. 12. FURTHER RESEARCH a) The mechanism(s) of phosgene toxicity need to be clarified in order to improve risk assessment and therapy. b) Data gaps in the areas of reproduction/development toxicity, mutagenicity and carcinogenicity following chronic low level exposure should be addressed. More data should be gained about the long-term effects of acute exposure. 13. 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Il existe des méthodes d'analyse pour la mise en évidence du phosgène dans l'air ou qui peuvent être utilisées dans le cadre des programmes d'hygiène et de sécurité du travail pour la mesure de la dose totale (par ex. ruban de papier indicateur). 1.2 Usages et sources d'exposition humaine et environnementale Le phosgène est utilisé à plus de 99% sur le lieu de production dans des systèmes clos. On le prépare en faisant réagir, en présence d'un catalyseur carboné, du chlore anhydre sur du monoxyde de carbone en proportions équimoléculaires. La production mondiale est estimée à plus de 3 millions de tonnes. La présence de phosgène dans l'environnement est due aux émissions d'origine industrielle et à la décomposition thermique des solvants et des polymères chlorés. Cependant, il peut également provenir en proportion importante de l'oxydation photochimique des chloréthylènes, comme le trichloréthylène et le tétrachloréthylène. 1.3 Transport, distribution et transformation dans l'environnement Le phosgène étant très réactif, il n'est vraisemblablement que peu transporté d'un compartiment à l'autre. Le phosgène s'élimine de l'air ambiant par une décomposition en phase hétérogène (catalyse de surface) et une lente hydrolyse en phase gazeuse. Il peut être transporté sur de longues distances et sa diffusion de la troposphère vers la stratosphère accélère probablement le processus de décomposition par photolyse. 1.4 Concentrations dans l'environnment et exposition humaine L'exposition humaine, qu'il s'agisse de la population générale ou de certaines catégories professionnelles, se produit par inhalation. La concentration moyenne du phosgène dans l'air ambiant peut varier d'environ 80 à 130 ng/m3, encore que les données soient peu nombreuses à ce sujet. En raison de la diversité des pratiques en matière d'hygiène du travail dans le monde, il est impossible de donner un chiffre pour caractériser l'exposition des travailleurs qui produisent ou utilisent du phosgène ou, plus particulièrement, l'exposition des pompiers. A l'heure actuelle, les valeurs-seuils (en moyenne pondérée par rapport au temps) relevées dans 15 pays s'étagent de 0,4 à 0,5 mg/m3. La littérature ne donne pas d'indications sur la teneur de l'eau, du sol et des aliments en phosgène. 1.5 Cinétique et métabolisme On ne possède que très peu de données sur l'absorption, le métabolisme, la distribution et la destinée du phosgène. La principale voie d'exposition est la voie respiratoire, le gaz pénétrant dans les tissus de l'arbre pulmonaire et ne se retrouvant par conséquent qu'en quantités minimes dans le reste de l'organisme. Sa demi-vie très brève (0,026 secondes) en solution aqueuse exclut toute rétention importante dans l'organisme. On ne dispose d'aucune donnée sur le métabolisme du phosgène. Ses produits d'hydrolyse, à savoir l'acide chlorhydrique et le dioxyde de carbone, sont éliminés de l'organisme par les processus physiologiques normaux. La toxicité du phosgène est due au fait qu'il provoque l'acylation des protéines et qu'il donne naissance à de l'acide chlorhydrique. Cette acylation se produit au niveau des groupements amino, hydroxyles et sulfhydriles des protéines et entraîne une inhibition marquée des enzymes qui interviennent dans le métabolisme énergétique ainsi qu'une rupture de la barrière air/sang. 1.6 Effets sur les animaux d'expérience et les systèmes d'épreuve in vitro 1.6.1 Exposition à court et à long terme Chez toutes les espèces étudiées, c'est le poumon qui est l'organe cible principal. La valeur du L(CT)50 varie de 900 mg/m3-min (225 ppm-min ) chez la souris à 1920 mg/m3-min (480 ppm-min) chez le cobaye. Une valeur de 1000 mg/ m3 (250 ppm-min) a été obtenue chez le singe. Chez toutes les espèces, on constate la même pathologie caractéristique, à savoir un oedème pulmonaire dont les manifestations cliniques sont retardées et qui est lié à la dose. Les anomalies anato-mopathologiques observées à faible concentration au niveau des bron-chioles terminales et des alvéoles, sont caractéristiques d'un irritant pulmonaire. En revanche, à forte concentration, l'oedème pulmonaire qui se développe perturbe les échanges gazeux et finit par entraîner la mort. On n'a pas connaissance d'études consacrées à une exposition de longue durée au phosgène. En ce qui concerne les durées d'exposition relativement courtes, on dispose d'une étude au cours de laquelle des rats on été exposés en une seule fois à du phosgène pendant 4 h à la concentration de 2 mg/m3. On a observé une réduction de l'immunocompétence pulmonaire mesurée par l'activité des cellules NK. Aucun effet n'a été constaté lors d'une exposition de 4 h à 0,4 mg/m3. Deux autres études ont été publiées au sujet des effets d'une exposition unique à du phosgène sur l'immunocompétence pulmo-naire. Au cours de ces études, effectuées sur des rats et des souris, on a constaté que des rats infectés par le virus grippal présentaient, après 4 h d'exposition à 4 mg de phosgène par m3, un titre viral 10 fois plus élevé 1 jour après l'infection, ce titre conservant une valeur élevée au cours des 4 jours suivants. En outre, chez les rats qui avaient été soumis pendant 4 h à une concentration de gaz comprise entre 0,2 et 4 mg/m3, on pouvait constater une diminution marquée du taux de prostaglandine E2 et de leucotriènes dès que la dose atteignait 0,4 mg/m3, avec réduction du nombre de macrophages alvéolaires et augmentation du nombre de neutrophiles à la concentration de 0,4 mg/m3. Pour étudier la résistance de l'hôte, on a soumis des souris à des concentrations de phosgène comprises entre 0,04 et 0,4 mg/m3 sur une durée de 4 h. On a constaté, selon les cas, une augmentation de la mortalité consécutive à une infection par Streptococcus zooepidemicus ou un accroissement des mélanomes pulmonaires B16/BL6 à partir de 0,1 mg/m3. Chez les rats exposés à du phosgène à raison de 0,4 mg/m3 (0,1 ppm) pendant 6 h ou à la même dose 6 h par jour, 5 j par semaine pendant 4 à 12 semaines , on a observé une réduction de la clairance bactérienne pulmonaire. L'effet était réversible après cessation de l'exposition. 1.6.2 Effets non pulmonaires Le phosgène peut provoquer une irritation oculaire et cutanée. On n'a pas trouvé trace, dans la littérature, d'études portant sur le pouvoir sensibilisateur du phosgène. On ne dispose d'aucune donnée relative aux effets du phosgène sur la reproduction et le développement. Il n'existe pas de données suffisantes pour permettre une évaluation du pouvoir mutagène ou cancérogène du phosgène. 1.7 Effets sur l'homme Chez l'homme, comme chez les animaux de laboratoire, l'organe cible est le poumon. Après exposition à des concentrations de phosgène comprises entre 120 et 1200 mg/m3-min , on a observé trois phases clinico-pathologiques distinctes. La phase initiale consiste en douleurs au niveau des yeux et de la gorge accompagnées d'une sensation de constriction thoracique, souvent avec dyspnée concomitante, respiration sifflante et toux; il peut également y avoir une hypo-tension, de la bradycardie et plus rarement, une arrythmie sinusale. La seconde phase ou phase de latence, souvent asymptomatique, peut se prolonger pendant 24 h , selon l'intensité et la durée de l'exposition. Au cours de la troisième phase, un oedème pulmonaire parfois mortel peut se développer. Dans des populations exposées au phosgène à la suite d'accidents industriels, on a fait état de symptômes très divers comme des céphalées, des nausées, de la toux, de la dyspnée, une fatigue générale, des maux de gorge, une sensation douloureuse de constriction thora-cique, des douleurs oculaires intenses et une forte lacrimation. Lors d'une étude, on a observé la survenue d'un oedème pulmonaire après une phase de latence de 48 h. Les effets d'une exposition au phosgène ont été étudiés chez des groupes de travailleurs de deux usines, à savoir une unité de production de phosgène et une unité de traitement de l'uranium. Dans les deux cas, on n'a effectué que des prélèvements d'air et une surveillance individuelle limités et l'exposition n'est donc connue que de manière estimative. L'examen du dossier médical de la totalité des 326 travailleurs de l'unité de production de phosgène qui pouvaient avoir été exposés à ce gaz (jusqu'à 0,5 mg/m3 avec quelques dépassements de cette valeur; moyenne 0,01 mg/m3) n'a pas révélé de problèmes pulmo-naires chroniques ni de surmortalité par comparaison avec un groupe témoin de 6226 personnes. Toutefois, l'absence de détails, dans le compte rendu, au sujet de l'exposition et des effets observés ne permet guère de tirer des conclusions définitives de cette étude. Dans le cas des travailleurs de l'usine de traitement de l'uranium, on a constitué deux groupes: l'un, de 699 personnes prises parmi les 1800 employés de cette période, a fait l'objet d'une étude transversale. Ces travailleurs avaient été vraisemblablement soumis à une concen-tration de phosgène inférieure à 0,4 mg/m3 (avec 4 ou 5 dépassements brefs par jour jusqu'à plus de 4 mg/m3). L'autre groupe était constitué de 106 personnes qui avaient été impliquées dans des accidents et soumises à une exposition de plus de 200 mg/m3-min. Dans le groupe exposé de manière chronique à de faibles concentrations de phosgène, l'examen des certificats de décès n'a pas fait ressortir de surmortalité due à une cause quelconque, à une affection respiratoire ou à un cancer du poumon. Il n'y a d'ailleurs eu aucune mortalité par cancer du poumon, mais par contre une légère surmortalité d'origine respiratoire. On ne peut tirer de ces études que des conclusions limitées sur les effets chroniques du phosgène et cela, tant du fait de l'absence de données sur l'exposition que pour des raisons d'ordre méthodologique. 1.8 Effets sur les autres êtres vivants au laboratoire et dans leur milieu naturel On ne possède aucun renseignement concernant les effets du phosgène sur les diverses formes vivantes présentes dans l'environnement. 1. RESUMEN Y CONCLUSIONES 1.1 Identidad, propiedades físicas y químicas y métodos analíticos El fosgeno es un gas incoloro y altamente reactivo a temperatura y presión ambientes. Posee un olor sofocante parecido al del heno enmohecido, que puede percibirse a concentraciones comprendidas entre 1,6 y 6 mg/m3. Existen métodos analíticos que permiten detectar el fosgeno en el aire y se utilizan en programas de higiene industrial que miden la dosis total (p.ej., sensores de cinta de papel). 1.2 Usos y fuentes de exposición humana y ambiental Más del 99% del fosgeno producido se emplea in situ en sistemas cerrados. Se produce haciendo reaccionar cantidades equimolares de cloro anhidro y monóxido de carbono en presencia de un catalizador de carbono. Se ha estimado que la producción mundial supera los 3 millones de toneladas. El fosgeno ambiental procede de emisiones industriales y de la degradación térmica de algunos disolventes clorados y polímeros clorados. No obstante, una fuente importante de fosgeno ambiental es la oxidación fotoquímica de cloroetilenos tales como el tri- y el tetraetileno. 1.3 Transporte, distribución y transformación en el medio ambiente Debido a su alta reactividad, el transporte intercompartimental del fosgeno es en principio limitado. La eliminación del fosgeno del aire ambiente se produce por descomposición heterogénea (catálisis superficial) y por hidrólisis lenta en fase gaseosa. El fosgeno es transportado a larga distancia, y se cree que su difusión de la troposfera a la estratosfera acelera su degradación fotolítica. 1.4 Niveles medioambientales y exposición humana La exposición humana tanto en la población general como en el entorno ocupacional se produce fundamentalmente por inhalación. Se estima que la concentración promedio de fosgeno en el aire ambiente está comprendida aproximadamente entre 80 y 130 ng/m3, aunque hay pocos datos disponibles. Dada la diversidad de las prácticas de higiene industrial seguidas en todo el mundo, es imposible facilitar una cifra para los trabajadores que fabrican o usan fosgeno o para los bomberos. Actualmente los valores umbral de exposición (promedio ponderado en función del tiempo) en 15 países están comprendidos entre 0,4 y 0,5 mg/m3. No se ha informado sobre las concentraciones de fosgeno en el agua, el suelo y los alimentos. 1.5 Cinética y metabolismo Hay muy pocos datos sobre la absorción, el metabolismo, la distribución y el destino del fosgeno. La principal vía de exposición es la inhalación; el gas penetra en los tejidos del tracto respiratorio, y sólo una mínima parte llega a distribuirse en el organismo. Su muy breve vida media (0,026 segundos) en soluciones acuosas evita que sea retenido significativamente por el organismo. No se ha publicado información alguna sobre el metabolismo del fosgeno. Sus productos hidrolíticos, p.ej. el ácido clorhídrico y el dióxido de carbono, son eliminados por el organismo mediante los procesos fisiológicos normales. El fosgeno debe su toxicidad a la acilación de las proteínas, así como a la generación de ácido clorhídrico. La acilación afecta a los grupos amino, hidroxilo y sulfhidrilo de las proteínas, lo que da lugar a una notable inhibición de varias enzimas relacionadas con el metabolismo energético y a la descomposición de la barrera sangre:aire. 1.6 Efectos en animales de laboratorio y en sistemas de prueba in vitro 1.6.1 Exposiciones únicas y de corta duración En todas las especies estudiadas el pulmón es el principal órgano blanco. La (CT)L50 varía entre 900 mg/m3-min (225 ppm-min) en el ratón y 1920 mg/m3-min (480 ppm-min) en el cobayo. Se ha informado de una (CT)L50 de 1000 mg/m3-min (250 ppm-min) en el mono. En todas las especies la manifestación patológica característica es la aparición retardada sintomática de edema pulmonar, que depende de la dosis. Los cambios anatomopatológicos observados en los bronquiolos terminales y en los alveolos a bajas concentraciones son típicos de los irritantes pulmonares, mientras que a exposiciones altas se produce edema, lo que interfiere en el intercambio gaseoso y conduce a la muerte. No se ha publicado ningún estudio sobre la exposición a largo plazo al fosgeno. Un estudio efectuado en ratas reveló que una sola exposición a una concentración de 2 mg/m3 de fosgeno durante 4 horas puede provocar una disminución de la inmunocompetencia pulmonar, a juzgar por la actividad citotóxica natural de las células pulmonares. No se observó ningún efecto a niveles de exposición de 0,4 mg/m3 mantenidos durante 4 horas. Se han publicado otros dos estudios sobre los efectos de exposiciones únicas de fosgeno en la inmunocompetencia pulmonar de la rata y del ratón. En ratas infectadas por el virus de la gripe tras 4 horas de exposición a 4 mg/m3 se observó que la concentración del virus se había multiplicado por diez un día después de la infección, manteniéndose significativamente elevados los niveles durante 4 días. Además, en ratas expuestas a concentraciones de fosgeno comprendidas entre 0,2 y 4 mg/m3 durante 4 horas se detectó una disminución considerable de la prostaglandina E2 y de los leucotrienos a partir de 0,4 mg/m3, y una disminución del número de macrófagos alveolares y un aumento del número de neutrófilos con 0,4 mg/m3. En un ensayo de resistencia en que se expuso a ratones a niveles de fosgeno comprendidos entre 0,04 y 0,4 mg/m3 durante 4 horas se observó un aumento de la mortalidad por Streptococcus zooepidemicus o un aumento del número de tumores pulmonares melanomatosos B16/BL6 a niveles de 0,1 mg/m3 o superiores. La eliminación bacteriana pulmonar se redujo en ratas expuestas a 0,4 mg/m3 (0,1 ppm) de fosgeno durante 6 horas o a 0,4 mg/m3 (0,1 ppm) durante 6 horas/día y 5 días/semana por espacio de 4 a 12 semanas. Este efecto se reveló reversible tras la terminación de la exposición. 1.6.2 Efectos no pulmonares La exposición al fosgeno puede causar irritación de los ojos y de la piel. No se ha hallado en las publicaciones ningún estudio referente al potencial de sensibilización del fosgeno. No se dispone de datos sobre los efectos del fosgeno en la reproducción y el desarrollo. No se dispone tampoco de datos adecuados para evaluar la mutagenicidad o carcinogenicidad del fosgeno. 1.7 Efectos en el hombre El órgano blanco en el hombre, como en los animales de laboratorio, es el pulmón. Se han descrito tres fases clinicopatológicas características tras la exposición a niveles de fosgeno comprendidos entre 120 y 1200 mg/m3-min. La fase inicial consiste en la aparición de dolor en los ojos y la garganta y de una sensación de opresión torácica, a menudo con disnea, sibilancias y tos; puede haber asimismo hipotensión, bradicardia y, rara vez, arritmias sinusales. La que sigue a continuación es la fase latente, porque es a menudo asintomática; puede durar hasta 24 horas según el nivel y duración de la exposición. En la tercera fase puede aparecer edema pulmonar, de consecuencias eventualmente mortales. Las poblaciones expuestas al fosgeno tras accidentes industriales han sufrido una amplia variedad de síntomas, incluidos cefaleas, náuseas, tos, disnea, fatiga, dolor faríngeo, opresión y dolor torácicos, dolor ocular intenso y lagrimeo grave. En un estudio se observó edema pulmonar tras una fase latente de 48 horas. Se han estudiado los efectos de la exposición al fosgeno a largo plazo en tres grupos de trabajadores de dos instalaciones: una planta de producción de fosgeno y un centro de procesamiento de uranio. En los dos casos el muestreo del aire y la vigilancia del personal se hicieron sólo de forma limitada, y únicamente se efectuaron estimaciones de la exposición de los trabajadores. El estudio de los registros médicos de los 326 trabajadores de la planta de producción de fosgeno potencialmente expuestos a este producto (concentraciones entre indetectables y de 0,5 mg/m3, valor éste superado sólo esporádicamente; promedio: 0,01 mg/m3) no reveló ni problemas pulmonares crónicos ni una mayor mortalidad por enfermedades respiratorias en comparación con un grupo de 6228 controles. No obstante, la falta de datos de que adolece el informe en lo que respecta a la exposición y a los efectos hace difícil extraer conclusiones firmes del estudio. Se estudió a dos grupos de trabajadores de la planta de procesamiento de uranio: una muestra transversal de 699 trabajadores de los más de 18 000 empleados durante el periodo estudiado, potencialmente expuestos a niveles de fosgeno inferiores a 0,4 mg/m3 (con 4 ó 5 exposiciones fugaces a niveles > 4 mg/m3 cada día), y un grupo de 106 trabajadores que se habían visto implicados en accidentes y expuestos a niveles > 200 mg/m3-min. En el grupo expuesto crónicamente a bajas concentraciones de fosgeno el análisis de los certificados de defunción no mostró una mayor mortalidad por todo tipo de causas o por enfermedad respiratoria o cáncer pulmonar. En el grupo afectado por accidentes químicos no se registró tampoco ningún aumento de las defunciones por todo tipo de causas; no hubo muertes por cáncer pulmonar, pero sí un ligero incremento del número de defunciones por enfermedades respiratorias. Habida cuenta tanto de la escasez de datos sobre la exposición como de la metodología del estudio, sus conclusiones tienen un valor limitado. 1.8 Efectos en otros organismos en el laboratorio y sobre el terreno No se han publicado datos sobre los efectos del fosgeno en organismos en el medio ambiente.
See Also: Phosgene (CHEMINFO) Phosgene (ICSC) Phosgene (PIM 419)