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<pre>      General remarks
      Health-based Reassessment of Administrative
      Occupational Exposure Limits
      Committee on Updating of Occupational Exposure Limits,
      a committee of the Health Council of the Netherlands
      No. 2000/15OSH/000, The Hague, 14 December 2000
000-1 General remarks
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<pre>000-2 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<pre>Chapter 1
        General introduction
1.1     Background of the project
        In September 1995, TNO Nutrition and Food Research Institute (Zeist, the
        Netherlands) reported the Minister of Social Affairs and Employment about the
        degree of health protection of the administrative occupational exposure limits
        (OELs) in the list of Maximal Accepted Concentrations (MAC) of 1994. The major
        part of these OELs were adopted from the American Conference of Governmental
        Industrial Hygienists' list of Threshold Limit Values in the 1970s. For the purpose
        of the evaluation concise toxicity profiles were prepared based on the
        documentation of the ACGIH and European criteria documents on almost 300
        substances. TNO concluded that for 109 substances the current OEL was
        suspected to be too high from a health protection point of view, with deviations
        ranging from a factor of 2 to 250. For another 106 substances the toxicological
        data base was judged to be too poor to recommend a health-based OEL.
            On September 24, 1996 the State Secretary of Social Affairs and Employment
        presented a plan to re-evaluate the administrative OELs to the Social and
        Economic Council. After the Social and Economic Council had given a positive
        reaction the State Secretary requested the Health Council on April 16, 1997, to
        re-evaluate these substances in a condensed procedure and to recommend
        health-based OELs. Given the international character of the request and in view
000-3   General introduction
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<pre>      of the European harmonization, the State Secretary requested the Health Council
      to invite scientists from outside the Netherlands to participate in the project.
1.2   Setting OELs in the Netherlands
      In the Netherlands the legally-binding occupational exposure limits for chemical
      substances are set using a three-step procedure. In the first step a scientific
      evaluation of the data on the toxicity of the substance is made by the Dutch
      Expert Committee on Occupational Standards (DECOS), a committee of the
      Health Council, on request of the State Secretary of Social Affairs and
      Employment. This evaluation should lead to a health-based recommended
      occupational exposure limit for the concentration of the substance in workroom
      air.*
           In the next phase of the three-step procedure the Social and Economic
      Council advises the State Secretary on the feasibility of using the health-based
      value as a legally-binding OEL, or recommends a different OEL. In the final step
      of the procedure the State Secretary sets the regulatory OEL.
           The three-step procedure will also be followed for health-based OELs derived
      in the present re-evaluation project.
1.3   Committee
      As a first step the Health Council requested several regulatory authorities of
      European countries to nominate internationally acknowledged experts in
      toxicology, epidemiology or occupational medicine with experience in setting
      OELs. All nominees were requested to send a brief curriculum vitae and a list of
      publications. The committee was selected from the list of nominees using the
      following criteria: one member from each foreign country, the expertise within the
      committee should cover all aspects of hazard assessment of chemical
      substances, and good spread in (former) affiliation of the members (academia,
      national institutes and industry). All members were invited on a personal title,
      except for the corresponding member representing ACGIH. The members of the
      Committee on Updating of occupational exposure limits are listed in Chapter 2.
*     For genotoxic carcinogens DECOS does not derive an OEL but presents an exposure-response
      relationship.
000-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>1.4   Procedure
      Under the authority of the Ministry of Social Affairs and Employment, for each
      substance a short document is prepared by a toxicologist at a research institute
      in the Netherlands. The requirements for the contents of these short documents
      were established by the committee during a trial phase*. The documents should
      be based on a full literature search including at least the data bases Medline,
      Toxline and Chemical Abstracts. From the published literature a key study is
      identified serving as the basis for deriving a health-based OEL. For extrapolation
      of the data (from the key study) to the occupational exposure situation an overall
      assessment factor is applied covering the aspects inter- and intraspecies
      variation, differences in duration and pattern of exposure between the key study
      and the situation of the worker, type of the critical effect, dose-effect relationship
      and quality of the total data base. In deriving the overall assessment factor the
      committee uses a check list of the different aspects, adopted from a TNO-report,
      to discuss and thoroughly weigh all available data. In each case the committee
      considers the appropriateness of applying default values, see Chapter 3. In case
      the key study refers to an oral animal experiment, scaling to humans is based on
      caloric demand (body weight to the power 0.75) rather than on body weight. For
      the recommendation of a health-based OEL the committee decided to make use of
      the preferred value system** given the inherent uncertainty of any OEL.
           To derive a health-based OEL for a substance at least data on acute toxicity,
      including irritation (and sensitization), and on repeated-dose toxicity are
      required. The committee considers as a minimum the availability of a multi-dose
      study in which a relevant animal species was exposed via a relevant exposure
      route for a relevant exposure time and in which relevant toxicological endpoints
      were studied (preferably including body weight gain, haematology, clinical
      biochemistry, gross and microscopic pathology). Preferably the study provides
      information about the target organ and critical effect, and produces a no
      observed adverse effect level.
*     The aims of this phase were to determine the requirements for the documents, to develop and test the
      procedure, and to judge the feasibility of the project. The fourteen substances under consideration during
      this phase were selected by the Ministry of Social Affairs and Employment in consultation with
      regulatory authorities in the participating countries.
**    The preferred value system implies that OELs are rounded up or down to ‘preferred values’, e.g. 0.1, 0.2,
      0.5, 1, 2, 5, 10 mg/m 3 etc.
000-5 General introduction
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<pre>          In case the data base is insufficient to recommend a health-based OEL the
      committee will strive to judge in a semi-quantitative way whether or not the
      current administrative limit is health-protective.
          Carcinogenic substances are not taken into consideration by the committee.
      When the data base of a substance indicates carcinogenic and/or genotoxic
      potential, the committee recommends an evaluation and classification of the
      substance by DECOS. For substances tested for and proven to be toxic to
      fertility or development, the committee ascertains that the recommended
      health-based OEL protects against these effects as well. For quite a number of
      substances, however, these data were not available.
          A draft of each document was released for public review during a period of
      six weeks and comments received were taken into account in the final version of
      the document.
          The Hague, 14 December 2000,
          for the committee
          dr CA Bouwman,                        prof. dr J Noordhoek
          scientific secretary                  chairman
000-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>Chapter 2
        The committee
           J Noordhoek, chairman †
           professor of toxicology; University of Nijmegen, Nijmegen, The Netherlands
           A Aitio
           senior scientist; International Programme on Chemical Safety, World Health
           Organization, Switzerland
           PL Chambers †
           co-ordinator toxicology studies; University of Dublin, Ireland
           VJ Feron
           professor of toxicology; TNO Nutrition and Food Research Institute,
           Zeist, The Netherlands
           H Greim
           professor of toxicology; GSF National Research Center for Environment
           and Health, Oberschleissheim, Germany
           U Hass
           senior researcher in toxicology; Institute of Food Safety and Toxicology;
           Søborg, Denmark
           CJ Högberg
           professor of toxicology; National Institute for Working Life and Karolinska
           Institutet, Stockholm, Sweden
000-7   The committee
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<pre>         G De Mik
         toxicologist; National Institute of Public Health and the Environment,
         Bilthoven, The Netherlands
         A Moses
         consultant toxicologist; Cheshire, United Kingdom
         W Seinen
         professor of toxicology; Utrecht University, Utrecht, The Netherlands
         GMH Swaen
         epidemiologist; University of Maastricht, Maastricht, The Netherlands
         WMD Wagner, corresponding member
         American Conference of Governmental Industrial Hygienists,
         Cincinnati, Ohio, USA
         RD Zumwalde
         senior scientist; National Institute for Occupational Safety and Health,
         Cincinnati, Ohio, USA
         LCMP Hontelez, advisor
         Ministry of Social Affairs and Employment, The Hague, The Netherlands
         WF Passchier, observer
         Health Council of the Netherlands, The Hague, The Netherlands
         CA Bouwman, scientific secretary
         Health Council of the Netherlands, The Hague, The Netherlands
000-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>Chapter 3
        Default values
        Adopted from the report ‘Methods for establishment of Health-based
        Recommended Occupational Exposure Limits for existing substances’, V96.463, 4
        July 1996, by TNO Nutrition and Food Research Institute, Zeist, the Netherlands
        (see also De Raat et al, Reg. Toxiol. Pharmacol. 25, 1997: 204-210).
         aspects                                              default value
         interspecies differences                             3
         intraspecies differences                             3
         differences between experimental conditions and      1-10
         exposure pattern of the worker
         type of critical effect                              1
         dose-response curve                                  1
         confidence of the data base                          1
000-9   Default values
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<pre>000-10 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<pre>Chapter 4
        Abbreviations
        Organisations and occupational exposure limits
        ACGIH       American Conference of Governmental Industrial Hygienists
        DECOS       Dutch Expert Committee on Occupational Standards
        DFG         Deutsche Forschungsgemeinschaft
        EPA         Environmental Protection Agency (USA)
        FDA         Food and Drug Administration (USA)
        HBR-OEL health based recommended occupational exposure limit
        HSE         Health and Safety Executive (UK)
        IARC        International Agency for Research on Cancer (WHO)
        IPCS        International Programme for Chemical Safety
        MAC         maximaal aanvaarde concentratie (maximal accepted concentration)
        MAK         Maximale Arbeitsplatz Konzentration
        MEL         maximum exposure limit
        NIOSH       National Institute for Occupational Safety and Health (USA)
        NTP         National Toxicology Programme (USA)
        OECD        Organisation for Economic Cooperation and Development
        OEL         occupational exposure limit
        OES         occupational exposure standard
        OSHA        Occupational Safety and Health Association (USA)
        PEL         permissible exposure limit
        REL         recommended exposure limit
        RTECS       Registry of Toxic Effects of Chemical Substances
        SCOEL       Scientific Committee for Occupational Exposure Limits
        SER         Social and Economic Council (Sociaal-Economische Raad NL)
        STEL        short term exposure limit
        TLV         threshold limit value
        TWA         time weighted average
        WHO         World Health Organisation
000-11  Abbreviations
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<pre>       Toxicological terms
       BALF          bronchio-alveolar lavage fluid
       bw            body weight
       CNS           central nervous system
       EC50          concentration at which a described effect is found in 50% of the exposed
                     animals or at which the effect is decreased up to 50% of the control value
       FCA           Freunds Complete Adjuvans
       FEV           forced expiratory volume
       FVC           forced vital capacity
       GD            gestation day(s)
       GPMT          guinea pig maximisation test
       GSH           glutathione
       h             hour
       IC50          concentration at which inhibition of a certain function is found up to 50% of
                     the control value
       im            intramuscular
       ip            intraperitoneal
       it            intratracheal
       iv            intravenous
       LC50          lethal concentration for 50% of the exposed animals
       LClo          lowest lethal concentration
       LD50          lethal dose for 50% of the exposed animals
       LDlo          lowest lethal dose
       LDH           lactate dehydrogenase
       LOAEL         lowest observed adverse effect level
       MAlvC         minimal alveolar concentration
       MFO           mixed function oxidase
       MMAD          mass median aerodynamic diameter
       MOAEL         minimal observed adverse effect level
       NOAEL         no observed adverse effect level
       n             number
       ppb           parts per billion (v/v)10-9
       ppm           parts per million (v/v)10-6
       PNS           peripheral nervous system
       po            per os (= oral)
       RBC           red blood cells
       RD50          concentration at which a 50% decrease of respiratory rate is observed
       SCE           sister chromatid exchange
       sc            subcutaneous
       UDS           unscheduled DNA-synthesis
       Vmax          maximal reaction velocity of an enzyme
       w             week
       Statistical terms
       CL            confidence limits
       GM            geometric mean
       OR            odds ratio
       RR            relative risk
       SD            standard deviation
       SEM           standard error of mean
       SMR           standard mortality ratio
000-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       Analytical methods
       BEI         biological exposure index
       GC          gas chromatography
       HPLC        high performance liquid chromatography
       MS          mass spectrometry
       NMR         nuclear magnetic resonance
       PAS         personal air sampling
       TLC         thin layer chromatography
000-13 Abbreviations
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<pre>000-14 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<br><br>