SELECTED NITRO- AND NITRO- OXY-POLYCYCLIC AROMATIC .

EHC 229: Selected Nitro- and Nitro-oxyPAHs8.3.2.2 Influence of polymorphisms onbiomarkers9.EFFECTS ON OTHER ORGANISMS IN THE LABORATORYAND FIELD3729.19.210.Laboratory experiments9.1.1 Aquatic species9.1.2 Biotransformation studies in aquaticspecies9.1.3 DNA damage in aquatic speciesField observations12.x372372372373375EVALUATION OF HUMAN HEALTH RISKS AND EFFECTSON THE ENVIRONMENT37610.1 Evaluation of human health risks10.1.1 Exposure levels10.1.1.1 NitroPAHs10.1.1.2 Nitroketones10.1.1.3 Nitrolactones10.1.2 Fate in the body10.1.2.1 NitroPAHs10.1.2.2 Nitroketones10.1.2.3 Nitrolactones10.1.3 Toxic effects10.1.3.1 Non-neoplastic effects10.1.3.2 Genotoxicity10.1.3.3 Neoplastic effects10.1.4 Evaluation of nitroPAHs,nitroketones and nitrolactones thatseem to be of importance in theenvironment10.2 Evaluation of effects on the environment10.3 General considerations10.4 Overall 81385386386390391RECOMMENDATIONS FOR PROTECTION OFHUMAN HEALTH AND THE ENVIRONMENT392RECOMMENDATIONS FOR FURTHER RESEARCH393

13.PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES394REFERENCES395RESUME448RESUMEN465xi

NOTE TO READERS OF THE CRITERIA MONOGRAPHSEvery effort has been made to present information in the criteriamonographs as accurately as possible without unduly delaying theirpublication. In the interest of all users of the Environmental HealthCriteria monographs, readers are requested to communicate any errorsthat may have occurred to the Director of the International Programmeon Chemical Safety, World Health Organization, Geneva, Switzerland,in order that they may be included in corrigenda.***The WHO Environmental Health Criteria Programme is financiallysupported by the US Environmental Protection Agency, EuropeanCommission, German Federal Ministry of the Environment, NatureConservation, and Nuclear Safety, and Japanese Ministry of Health,Labour and Welfare.xii

Environmental Health CriteriaObjectivesIn 1973, the WHO Environmental Health Criteria Programme wasinitiated with the following objectives:(i)to assess information on the relationship between exposure toenvironmental pollutants and human health, and to provideguidelines for setting exposure limits;(ii)to identify new or potential pollutants;(iii)to identify gaps in knowledge concerning the health effects ofpollutants;(iv)to promote the harmonization of toxicological and epidemiological methods in order to have internationally comparableresults.The first Environmental Health Criteria (EHC) monograph, onmercury, was published in 1976, and since that time an ever-increasingnumber of assessments of chemicals and of physical effects have beenproduced. In addition, many EHC monographs have been devoted toevaluating toxicological methodology, e.g. for genetic, neurotoxic,teratogenic and nephrotoxic effects. Other publications have beenconcerned with epidemiological guidelines, evaluation of short-termtests 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 healtheffects, has been increasingly emphasized in the total evaluation ofchemicals.The original impetus for the Programme came from World HealthAssembly resolutions and the recommendations of the 1972 UNConference on the Human Environment. Subsequently the workbecame an integral part of the International Programme on Chemical

Safety (IPCS), a cooperative programme of UNEP, ILO and WHO. Inthis manner, with the strong support of the new partners, theimportance of occupational health and environmental effects was fullyrecognized. The EHC monographs have become widely established,used and recognized throughout the world.The recommendations of the 1992 UN Conference on Environmentand Development and the subsequent establishment of theIntergovernmental Forum on Chemical Safety with the priorities foraction in the six programme areas of Chapter 19, Agenda 21, all lendfurther weight to the need for EHC assessments of the risks ofchemicals.ScopeThe criteria monographs are intended to provide critical reviews onthe effects on human health and the environment of chemicals and ofcombinations of chemicals and physical and biological agents. Assuch, they include and review studies that are of direct relevance forthe evaluation. However, they do not describe every study carried out.Worldwide data are used and are quoted from original studies, not fromabstracts or reviews. Both published and unpublished reports areconsidered, and it is incumbent on the authors to assess all the articlescited in the references. Preference is always given to published data.Unpublished data are used only when relevant published data areabsent or when they are pivotal to the risk assessment. A detailedpolicy statement is available that describes the procedures used forunpublished proprietary data so that this information can be used inthe evaluation without compromising its confidential nature (WHO(1990) Revised Guidelines for the Preparation of Environmental HealthCriteria 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 vitrostudies provide support and are used mainly to supply evidencemissing from human studies. It is mandatory that research on humansubjects is conducted in full accord with ethical principles, includingthe provisions of the Helsinki Declaration.xiv

The EHC monographs are intended to assist national andinternational authorities in making risk assessments and subsequentrisk management decisions. They represent a thorough evaluation ofrisks and are not, in any sense, recommendations for regulation orstandard setting. These latter are the exclusive purview of national andregional governments.ContentThe layout of EHC monographs for chemicals is outlined below. Summary — a review of the salient facts and the risk evaluation ofthe chemicalIdentity — physical and chemical properties, analytical methodsSources of exposureEnvironmental transport, distribution and transformationEnvironmental levels and human exposureKinetics and metabolism in laboratory animals and humansEffects on laboratory mammals and in vitro test systemsEffects on humansEffects on other organisms in the laboratory and fieldEvaluation of human health risks and effects on the environmentConclusions and recommendations for protection of human healthand the environmentFurther researchPrevious evaluations by international bodies, e.g., IARC, JECFA,JMPRSelection of chemicalsSince the inception of the EHC Programme, the IPCS has organizedmeetings of scientists to establish lists of priority chemicals forsubsequent evaluation. Such meetings have been held in Ispra, Italy,1980; Oxford, United Kingdom, 1984; Berlin, Germany, 1987; and NorthCarolina, USA, 1995. The selection of chemicals has been based on thefollowing criteria: the existence of scientific evidence that thesubstance presents a hazard to human health and/or the environment;the possible use, persistence, accumulation or degradation of thexv

substance shows that there may be significant human or environmentalexposure; the size and nature of populations at risk (both human andother species) and risks for environment; international concern, i.e., thesubstance is of major interest to several countries; adequate data onthe hazards are available.If an EHC monograph is proposed for a chemical not on the prioritylist, the IPCS Secretariat consults with the Cooperating Organizationsand all the Participating Institutions before embarking on thepreparation of the monograph.ProceduresThe order of procedures that result in the publication of an EHCmonograph is shown in the flow chart on p. xvii. A designated staffmember of IPCS, responsible for the scientific quality of the document,serves as Responsible Officer (RO). The IPCS Editor is responsible forlayout and language. The first draft, prepared by consultants or, moreusually, staff from an IPCS Participating Institution, is based onextensive literature searches from reference databases such as Medlineand Toxline.The draft document, when received by the RO, may require aninitial review by a small panel of experts to determine its scientificquality and objectivity. Once the RO finds the document acceptable asa first draft, it is distributed, in its unedited form, to well over 150 EHCcontact points throughout the world who are asked to comment on itscompleteness and accuracy and, where necessary, provide additionalmaterial. The contact points, usually designated by govern ments, maybe Participating Institutions, IPCS Focal Points or individual scientistsknown for their particular expertise. Generally some four months areallowed before the comments are considered by the RO and author(s).A second draft incorporating comments received and approved by theDirector, IPCS, is then distributed to Task Group members, who carryout the peer review, at least six weeks before their meeting.xvi

EHC PREPARATION FLOW CHARTCommitmentCommitment toto draftdraft EHCEHCDocument preparation initiatedRevision asnecessaryDraft sent to IPCS Responsible Officer (RO)Possible meetingof a few expertsto resolvecontroversial xtandandreadability (not language editing)readability (not language editing)FirstFirst DraftDraftInternational circulation to Contact Points (150 )Comments to IPCS (RO)Review of comments, reference cross-check;preparation of Task Group (TG) draftEditorWorking group,if requiredTask Group meetingInsertion of TG changesPost-TG draft; detailed reference nslations of SummaryWord-processingLibrary forCIP DataCamera-ready copyFinal editingApproval by Director, IPCSWHO Publication Officeroutine procedureoptional procedurePrinterProofsPublicationPublicationxvii

The Task Group members serve as individual scientists, not asrepresentatives of any organization, government or industry. Theirfunction is to evaluate the accuracy, significance and relevance of theinformation 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 alsorequired. The composition of the Task Group is dictated by the rangeof expertise required for the subject of the meeting and by the need fora balanced geographical distribution.The three cooperating organizations of the IPCS recognize theimportant role played by nongovernmental organizations. Representatives from relevant national and international associations may beinvited to join the Task Group as observers. Although observers mayprovide a valuable contribution to the process, they can speak only atthe invitation of the Chairperson. Observers do not participate in thefinal evaluation of the chemical; this is the sole responsibility of theTask Group members. When the Task Group considers it to beappropriate, it may meet in camera.All individuals who as authors, consultants or advisers participatein the preparation of the EHC monograph must, in addition to servingin their personal capacity as scientists, inform the RO if at any time aconflict of interest, whether actual or potential, could be perceived intheir 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 issatisfied as to the scientific correctness and completeness of thedocument, it then goes for language editing, reference checking andpreparation of camera-ready copy. After approval by the Director, IPCS,the monograph is submitted to the WHO Office of Publications forprinting. At this time, a copy of the final draft is sent to the Chairpersonand Rapporteur of the Task Group to check for any errors.It is accepted that the following criteria should initiate the updatingof an EHC monograph: new data are available that would substantiallychange the evaluation; there is public concern for health orxviii

environmental effects of the agent because of greater exposure; anappreciable time period has elapsed since the last evaluation.All Participating Institutions are informed, through the EHCprogress report, of the authors and institutions proposed for thedrafting of the documents. A comprehensive file of all commentsreceived on drafts of each EHC monograph is maintained and isavailable on request. The Chairpersons of Task Groups are briefedbefore each meeting on their role and responsibility in ensuring thatthese rules are followed.xix

WHO TASK GROUP ON ENVIRONMENTAL HEALTHCRITERIA FOR SELECTED NITRO- AND NITRO-OXYPOLYCYCLIC AROMATIC HYDROCARBONSMembersProfessor D. Anderson, Department of Biomedical Sciences,University of Bradford, Bradford, West Yorkshire, UnitedKingdom (Chairperson)Professor J. Arey, Air Pollution Research Center, University ofCalifornia, Riverside, California, USADr R.P. Bos, Department of Pharmacology & Toxicology, UMC St.Radboud, University of Nijmegen, Nijmegen, The NetherlandsDr A. Cecinato, Istituto sull’Inquinamento Atmosferico-CNR, CP10Monterotondo Stazione, Rome, ItalyDr K. El-Bayoumy, Division of Cancer Etiology & Prevention,American Health Foundation, Valhalla, New York, USA (ViceChairperson)Dr P.C. Howard, Division of Biochemical Toxicology, National Centerfor Toxicological Research, Jefferson, Arkansas, USA (CoRapporteur)Dr J. Kielhorn, Chemical Risk Assessment, Fraunhofer Institute ofToxicology and Aerosol Research, Hanover, Germany (CoRapporteur)Professor M. Kirsch-Volders, Laboratory of Cell Genetics, FreeUniversity of Brussels, Brussels, BelgiumDr I. Mangelsdorf, Chemical Risk Assessment, Fraunhofer Instituteof Toxicology and Aerosol Research, Hanover, Germanyxx

Dr S. Pavittranon, Toxicology and Environmental Laboratory,National Institute of Health, Department of Medical Sciences,Ministry of Public Health, Nontaburi, ThailandDr H. Tokiwa, Department of Environmental Health Science, KyushuWomen’s University, Kitakyushu, JapanDr U. Wahnschaffe, Consultant, Uetze, GermanyProfessor Z. Yuxin, Institute of Occupational Medicine, ChineseAcademy of Preventive Medicine, Beijing, People’s Republic ofChinaSecretariatMr T. Ehara, International Programme on Chemical Safety, WorldHealth Organization, Geneva, SwitzerlandMrs P. Harlley, International Programme on Chemical Safety, WorldHealth Organization, Geneva, Switzerlandxxi

ENVIRONMENTAL HEALTH CRITERIASELECTED NITRO- AND NITRO-OXY-POLYCYCLICAROMATIC HYDROCARBONSThe first and second drafts of this monograph were prepared bythe authors, Drs J. Kielhorn, U. Wahnschaffe and I. Mangelsdorf.A WHO Task Group on Environmental Health Criteria for SelectedNitro- and Nitro-oxy-Polycyclic Aromatic Hydrocarbons met at theFraunhofer Institute of Toxicology and Aerosol Research, in Hanover,Germany, on 26–30 November 2001. The group reviewed the draft andthe peer review comments, revised the draft and made an evaluation ofthe risks for human health and environment from exposure to selectednitro- and nitro-oxy-polycyclic aromatic hydrocarbons.Dr P. Jenkins and Mr T. Ehara of the IPCS central unit wereresponsible for the scientific aspects of the monograph, and Ms. MarlaSheffer was responsible for the technical editing.The efforts of all, especially the Fraunhofer Institute of Toxicologyand Aerosol Research, which helped in the preparation and finalizationof the monograph, are gratefully acknowledged.xxii

ACRONYMS AND aminoBaPdIDMSODNADNPbenzo[a]pyrenebody weightChemical Abstracts Servicecomplementary (or copy) DNAChinese hamster ovarycytochrome P450no. 2 diesel 10-tetrahydro-1nitrobenzo[a]pyrene10-(deoxy zo[a]pyrenedeoxyinosinedimethyl sulfoxidedeoxyribonucleic aciddinitropyrenexxiii

100LD50LOAELxxivelectron capturemedian effective concentrationelectron capture detectormedian effective doseEnvironmental Health Criteria monographelectron impactenzyme-linked immunosorbent assayEnvironmental Protection Agency (USA)Food and Agriculture Organization of theUnited NationsFederal Test Procedure (USA)gas chromatographysemipreparative gel permeationchromatographyglutathione -duty dieselhigh-performance liquid chromatographyInternational Agency for Research onCancerInternational Labour nal Programme on ChemicalSafetyintravenousJoint FAO/WHO Expert Committee onFood AdditivesJoint FAO/WHO Meeting on PesticideResiduesorganic carbon/water partition coefficientn-octanol/water partition coefficientmedian lethal concentrationlethal concentration for 100% of testorganismsmedian lethal doselowest-observed-adverse-effect level

LOEL

EHC 229: Selected Nitro- and Nitro-oxyPAHs vi 6.2 1-Nitropyrene metabolism in mammals 125 6.2.1 Absorption 125 6.2.2 Distribution 125 6.2.3 Metabolism 126 6.2.3.1 Introduction 126 6.2.3.2 Identification of metabolites 126 6.2.3.3 Cytochrome P450-mediated ring C-oxidative pathway 137 6.2.3.