<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>Iron and steel
founding emissions
Evaluation of the carcinogenicity and genotoxicity
To: The State Secretary of Social Affairs and Employment
No. 2020/02, The Hague, February 18, 2020
                                                         2 2
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<pre> Contents                                                                                    Iron and steel founding emissions | page 2 of 87
 contents
      Samenvatting4                                                 03 International classification                                     14
                                                                        3.1  European Commission                                          15
      Executive summary                                           6    3.2  IARC                                                         15
                                                                        3.3  The Health Council of the Netherlands                        15
 01 Scope8
      1.1  Background                                             9 04 Monitoring                                                       16
      1.2  Committee and procedure                                9    4.1  Environmental exposure monitoring                            17
      1.3  Data                                                   9    4.2  Biological exposure monitoring                               17
      1.4  Quality assessment                                    10
      1.5  Criteria for classification                           10 05 Manufacture and uses                                             18
                                                                        5.1  Manufacture                                                  19
 02 Identity of the iron and steel founding emissions            11    5.2  Identified uses                                              19
      2.1  Iron and steel founding                               12
      2.2  Composition of the iron and steel founding emissions  13 06 Summary of (toxico)kinetics                                      20
      2.3  Physicochemical properties                            13
1       Health Council of the Netherlands | No. 2020/02                                                    2                                3
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<pre> Contents                                                                                    Iron and steel founding emissions | page 3 of 87
 07 Germ cell mutagenicity                                          22  Annexes37
      7.1  Summary and relevance of the provided information on          A  IARC evaluation and conclusion                                    38
           (germ cell) mutagenicity                                  23 B  Reliability testing of animal and in vitro studies                40
      7.2  Evaluation of the germ cell mutagenicity                  25 C  Reliability testing of epidemiological studies                    41
      7.3  Recommendation on the classification for                      D  Classification on germ cell mutagenicity                          43
           germ cell mutagenicity                                    25 E  Classification on carcinogenicity                                 48
                                                                         F  Individual components that can be found in the emission
 08 Carcinogenicity26                                                      during iron and steel founding                                    49
      8.1  Summary and relevance of the provided information on          G  Substances identified in the emissions of iron and steel founding,
           carcinogenicity27                                               which are classified for carcinogenicity                          53
      8.2  Evaluation of the carcinogenicity                         30 H  Genotoxicity: mutagenicity x                                      55
      8.3  Recommendation on the classification for carcinogenicity 30  I  Genotoxicity in humans                                            58
                                                                         J  Epidemiology: meta-analyses                                       63
      References31                                                      K  Epidemiology: cohorts studies                                     66
                                                                         L  Epidemiology: case-control studies                                83
2       Health Council of the Netherlands | No. 2020/02                                                     2                                   4
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<pre> Samenvatting                                                                                            Iron and steel founding emissions | page 4 of 87
 samenvatting
 Op verzoek van de Minister van Sociale Zaken          Het gieten van ijzer en staal                    Beoordeling kankerverwekkende en
 en Werkgelegenheid heeft de Gezondheidsraad           In dit advies worden de emissies die ontstaan    mutagene eigenschappen
 beoordeeld of emissies die ontstaan tijdens het       tijdens het ijzer- en staalgieten in ogenschouw  De commissie beoordeelt aan de hand van de
 ijzer- en staalgieten een genotoxisch effect          genomen. Individuele stoffen die in de emissie   beschikbare wetenschappelijk literatuur of er
 hebben en tot kanker kunnen leiden.                   tijdens het ijzer- en staalgietproces kunnen     aanwijzingen zijn dat individuele stoffen,
 Het advies is opgesteld door de Subcommissie          voorkomen worden niet afzonderlijk beoordeeld.   mengsels of emissies genotoxisch en
 Classificatie kankerverwekkende stoffen –             Het ijzer- en staalgietproces omvat het maken    kankerverwekkend zijn en hoe groot de
 hierna aangeduid als de commissie –,                  van mallen, het smelten en behandelen van de     bewijskracht daarvoor is. Genotoxische stoffen
 een subcommissie van de vaste commissie               basismaterialen, het gieten in mallen, het laten met mutagene eigenschappen kunnen het
 Gezondheid en beroepsmatige blootstelling             afkoelen van het gegoten materiaal en het        erfelijk materiaal in de cel blijvend veranderen
 aan stoffen. De samenstelling van de                  verwijderen van de mallen en het afwerken van    (mutatie of genafwijking). Hierdoor kunnen zij
 subcommisie is te vinden achterin dit advies.         het gietsel. De ijzer- en staalproducten die     kankerverwekkend zijn. Aan de hand van de
 De Gezondheidsraad heeft een vaste rol bij            hieruit voorkomen kennen een brede toepassing    bewijskracht doet de commissie vervolgens
 de bescherming van werknemers tegen                   in onder meer de auto- en scheepvaartindustrie,  voorstellen om de stof te classificeren in
 mogelijke schadelijke effecten van stoffen waar       constructie-industrie en verpakkingsindustrie.   gevarencategorieën: één die aangeeft hoe groot
 zij tijdens hun werk mee in aanraking kunnen                                                           de bewijskracht is dat de stof mutageen is in
 komen. Meer informatie over die rol staat op                                                           geslachtscellen, en één die aangeeft hoe groot
 www.gezondheidsraad.nl.                                                                                de bewijskracht is dat de stof tot kanker kan
3         Health Council of the Netherlands | No. 2020/02                                                              2                                 5
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<pre> Samenvatting                                                                                           Iron and steel founding emissions | page 5 of 87
 leiden. De categorieën zijn gebaseerd op de          Advies aan de minister
 criteria die gebruikt worden in EU-verordening       Op basis van de beschikbare gegevens beveelt
 (EG) 1272/2008 over de classificatie van stoffen.    de commissie aan de emissies van ijzer- en
 Op basis van de voorstellen van de commissie         staalgieten te classificeren als mutageen in
 kan de minister besluiten om de stof al dan niet     geslachtscellen in categorie 2 (“stof die reden
 als mutageen in geslachtscellen en/of als            geeft tot bezorgdheid voor de mens omdat zij
 kankerverwekkend aan te merken.                      mogelijk erfelijke mutaties in de geslachtscellen
                                                      van mensen veroorzaakt”).
                                                      De commissie concludeert dat beroepsmatige
                                                      blootstelling aan de emissies van ijzer- en
                                                      staalgieten kankerverwekkend zijn voor de
                                                      mens, en beveelt aan deze emissies in
                                                      categorie 1A (“stof is kankerverwekkend voor de
                                                      mens”) te classificeren. De kankerverwekkende
                                                      effecten worden waarschijnlijk veroorzaakt
                                                      door een stochastisch genotoxisch werkings­
                                                      mechanisme.
4        Health Council of the Netherlands | No. 2020/02                                                             2                                 6
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<pre> Executive summary                                                                                      Iron and steel founding emissions | page 6 of 87
 executive summary
 At request of the Minister of Social Affairs and    Iron and steel founding                           Assessment of genotoxicity and
 Employment, the Health Council of the               In the present advisory report, the evaluation    carcinogenicity
 Netherlands assessed whether emissions,             concerns the emissions that are formed during     Based on the available scientific literature, the
 which are formed during iron and steel founding,    the iron and steel founding. Individual           committee assesses the potential genotoxic
 may induce genotoxic effects and may cause          substances that can be found in the emissions     and carcinogenic properties of individual
 cancer. The assessment is performed by the          are not considered. Iron and steel founding       substances, mixtures or emissions. If there are
 Subcommittee on Classifying carcinogenic            comprises creating a mould, melting and           indications for such properties, it recommends
 substances – hereafter called the committee –       treating the basic material, pouring into moulds, classifying the substance in two hazard
 of the Dutch Expert Committee on Occupational       cooling down the metal, and removing and          categories, which represent the grade of
 Safety of the Health Council. The membership        cleaning the castings. Iron and steel products    evidence that the substance is mutagenic in
 of the Subcommittee is given on the last page of    are widely used, such as in the car and shipping  germ cells (a measure for genotoxicity), and that
 this advisory report. The Health Council has a      industry, construction industry and the           the substance is carcinogenic. The categories
 permanent task in the protection of employees to    packaging industry.                               are based on the criteria for assessing hazard
 harmful health effects of substances to which                                                         categories, as set by the European Commission
 they may be exposed during work. More                                                                 (EU-guideline (EG) 1272/2008).
 information on this task can be found on the                                                          The recommendation can be used by the
 website www.gezondheidsraad.nl.                                                                       Minister to decide whether the substance should
                                                                                                       be listed as mutagenic in germ cells and/or
                                                                                                       carcinogenic.
5       Health Council of the Netherlands | No. 2020/02                                                               2                                  7
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<pre> Executive summary                                      Iron and steel founding emissions | page 7 of 87
 Recommendation
 Based on the available data, the Committee
 recommends classifying iron and steel founding
 emissions as a germ cell mutagen in category 2
 (“Substances which cause concern for humans
 owing to the possibility that they may induce
 heritable mutations in the germ cells of
 humans”).
 The committee concludes that iron and steel
 founding emissions are carcinogenic to humans,
 and recommends classifying the emissions in
 category 1A (“known to have carcinogenic
 potential for humans”). The carcinogenic effects
 are most likely caused by a stochastic genotoxic
 mode of action.
6       Health Council of the Netherlands | No. 2020/02              2                                 8
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<pre> chapter 01 | Scope                                    Iron and steel founding emissions | page 8 of 87
 01
 scope
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<pre> chapter 01 | Scope                                                                                        Iron and steel founding emissions | page 9 of 87
 1.1 Background                                                               The members of the committee, including the consulted experts, are listed
 In the Netherlands a special policy is in force with respect to occupational on the last page of this report.
 use and exposure to carcinogenic substances. Regarding this policy, the
 Minister of Social Affairs and Employment has asked the Health Council of    In 2018, the President of the Health Council released a draft of the report
 the Netherlands to evaluate the carcinogenic properties of substances        for public review. The committee has taken these comments into account
 (individual substances, mixtures or emissions), and to propose a             in deciding on the final version of the report. The comments, and the replies
 classification. In addition to classifying substances as carcinogenic, the   by the committee, can be found on the website of the Health Council.
 Health Council also assesses the genotoxic properties of the substance
 in question, and proposes a classification on germ cell mutagenicity.        1.3 Data
 A letter of the request can be found on the website of the Health Council.   The evaluation and recommendation of the committee is standardly based
                                                                              on scientific data, which are publicly available. The starting points of the
 This report contains the evaluation of the mutagenicity and carcinogenicity  committees’ reports are, if possible, the monographs of the International
 of the emissions that are formed during iron and steel founding. Iron and    Agency for Research on Cancer (IARC). This means that the original
 steel founding comprises creating a mould, melting and treating the basic    sources of the studies, which are mentioned in the IARC-monograph,
 material, pouring into moulds, cooling down the metal, and removing          are evaluated only by the committee when these are considered most
 and cleaning the castings. The evaluation concerns the emissions as a        relevant in assessing the carcinogenicity and genotoxicity of the
 whole. Individual substances that can be found in the emissions are not      substance in question. In the case of iron and steel founding emissions,
 considered.                                                                  such an IARC-monograph is available, of which the summary and
                                                                              conclusion is inserted in Annex A.
 1.2 Committee and procedure
 The evaluation is performed by the Subcommittee on Classifying               Data published after the last IARC evaluation were retrieved from the
 Carcinogenic Substances of the Dutch Expert Committee on                     online databases Medline, Toxline, Chemical Abstracts, and RTECS.
 Occupational Safety of the Health Council, hereafter called the committee.   The last online search was in August 2019. The literature search was
8        Health Council of the Netherlands | No. 2020/02                                                                 2                                 10
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<pre> chapter 01 | Scope                                                                                     Iron and steel founding emissions | page 10 of 87
 based on the following key words: foundry or foundries, iron foundry/       the Committee considers them useful in recommending a classification as
 foundries, steel foundry/foundries, occupational exposure, cancer,          mutagenic in germ cells for substances, mixtures and emissions, for which
 carcinog*, mutag*, genotox*. All data retrieved (i.e., data from the IARC   the regulation does not apply. The criteria are based on the Globally
 Monograph and new data) were summarized in tables in the annexes of         Harmonized System, and can be universally applied.
 the present advisory report.
                                                                             In 2010, the Health Council published a Guideline to the classification of
 1.4 Quality assessment                                                      carcinogenic compounds, for classifying substances in terms of their
 The Committee evaluates the data retrieved on reliability and quality,      carcinogenic properties, and for assessing the mode of action.4
 by using criteria set by others, and by expert judgment. For animal         The criteria and the classification on carcinogenic properties are based
 experiments and in vitro assays, the criteria set by Klimisch et al. (1997) on the Globally Harmonized System, which is also used by the European
 are used.1 For epidemiological studies, the reliability criteria set by     Union for the classification, labelling and packaging of substances and
 Money et al. (2013) are used.2 A summary of the reliability criteria is     mixtures (Regulation EC 1272/2008, Section 3.6 Carcinogenicity).3
 given in Annex B and C, respectively.                                       Annex E summaries the classification system for carcinogenic
 In Chapter 7 and 8, studies with sufficient reliability (with or without    substances, as used by the Committee. For the assessment of the
 restrictions) are described, and taken into account for the hazard          carcinogenicity, the Committee uses four categories of evidence.
 assessment. Studies with lower quality are incorporated in the summary      These categories are described in detail in the Guideline to the
 tables in the annexes, but not considered for the hazard assessment.        classification of carcinogenic compounds (Health Council, 2010).4
                                                                             The proposal for a classification is expressed in standard sentences,
 1.5 Criteria for classification                                             combined with a category number.
 For recommending a classification on mutagenicity in germ cells, the
 Committee uses the criteria described in Section 3.5 of Annex I of the
 European regulation No. 1272/2008 (see annex D), in combination with
 expert judgement.3 Although the criteria mentioned in the regulation are
 set for substances that are evaluated according to the CLP-regulation,
9        Health Council of the Netherlands | No. 2020/02                                                               2                                11
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<pre> chapter 02 | Identity of the iron and steel founding emissions Iron and steel founding emissions | page 11 of 87
 02
 identity of the iron and
 steel founding emissions
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<pre> chapter 02 | Identity of the iron and steel founding emissions                                           Iron and steel founding emissions | page 12 of 87
 The information in this chapter is abstracted from IARC Monographs.5-7           make the product. Natural bonding or synthetic sand casting is one of
                                                                                  the simplest types of casting. The sand is bonded together using clays,
 2.1 Iron and steel founding                                                      chemical binders (e.g., furan, phenolic isocyanate, sulphonic acids) or
 The present evaluation concerns the occupational exposure to the                 polymerized oils and resins (e.g., urea-formaldehyde, polyester
 emissions that are formed during iron and steel founding operations.             urethane). Also, organic additives to control for the atmosphere are
 No distinction is made between iron founding and steel founding; steel is        added in the (green-sand) moulds, such as pulverized coal dust or
 an alloy of iron and carbon. The differences in composition and founding         coal-dust replacements (e.g., synthetic polymers (such as polysterene,
 operations between iron and steel founding fall within the general diversity     polymeric petroleum ­products), products of coal or petroleum distillation
 in materials and founding processes of ferrous materials.                        (e.g., mixture of heavy hydrocarbons, aromatic components and
                                                                                  naphthenes), asphalts (bitumen), and coal-tar pitches. Moulds can be
 In short, iron and steel founding comprises patternmaking, creating a            produced for single (disposable, non-reusable) or permanent use.
 mould, melting and pouring the melted metals in moulds, and fettling:          • Melting and pouring. So-called cupolas (iron casting; charge material,
 • Patternmaking. A pattern is a three-dimensional negative image of the          pig iron and scrap), electric-induction furnaces (iron and steel casting),
    desired product. The materials and design of the pattern depend upon          electric arc furnaces (steel casting; open-heart and reverberatory
    the method of casting production, and the intended shape of the               furnaces), or combinations are used to melt iron and steel. Holding
    desired product. Materials used to make patterns may include wood,            furnaces may serve as a reservoir of the melted metal at the pouring
    natural and synthetic waxes or polystyrene foam materials.                    temperature. To get the desired composition of the desired product,
    Patterns are created for single (expendable) or permanent use.                additional charge materials existing of ferroalloys of pure metal are
 • Creating a mould. Using the patterns, a mould or matrix, which contains        added, such as ferrochromium and ferromanganese. In addition,
    a hollow negative image of the desired product, is made from sand             calcium compounds (e.g., calcium silicide, calcium carbide), and
    (silica (quartz) or bentonite), metal or other materials, which do not melt   magnesium metal may be added to control the melting and casting.
    together with the melted iron or steel, and which does not distort during     The scrap may contain undesired metal constituents, such as lead,
    the moulding process. The choice of material depends on the desired           zinc and cadmium, which are evaporated during melting, together with
    size of the product, the production volume, and type of metal needed to       pyrolysis products of any oil, grease, plastics or rubber present in the
11        Health Council of the Netherlands | No. 2020/02                                                                2                                 13
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<pre> chapter 02 | Identity of the iron and steel founding emissions                                          Iron and steel founding emissions | page 13 of 87
    charge material. During the melting process, reagents may be added to     the emissions of iron and steel founding, are for instance respirable
    purify, deoxidise, degas, inoculate or refine the alloy. Furnace          (metal) dust and quartz, carbon monoxide and carbon dioxide, aliphatic
    temperatures are about 1,400 (cast irons) degrees Celsius or higher.      hydrocarbons (e.g., benzene), and organic binder materials (e.g.,
    The pouring is a delicate process, in which the pouring rate and          isocyanates, phenol, formaldehyde, various amines). In airborne pyrolysis
    temperature are crucial factors to prevent deterioration of the mould     products (coal tar pitch) substantial quantities of polycyclic aromatic
    and casting. To minimize a temperature drop of the melted metal, a        compounds can be found, such as pyrene and benzo(a)pyrene. A list of
    preheating system is used. During and after pouring, lighting and gas     the main substances to which workers are likely exposed during iron and
    evolving from the hot mould may enter the workplace atmosphere.           steel founding is given by IARC (1984; see also Annex F of the present
    When cooled down, the moulds are shaked-out by, for instance,             advisory report).5 In the more recently published IARC Monograph (2012),
    pneumatic tools, hammers, and vibratory tables, during which dust         a new summary description is given of the main substances in
    exhaust may be released into the workplace atmosphere.                    combination with data on exposure levels: respirable dust and respirable
 • Fettling. After the shake-out, the finished casting is cleaned by          quartz, carbon monoxide, binder compounds, polycyclic aromatic
    removing adherent sand residues (manually or mechanically), and           hydrocarbons, metals, and/or refractory ceramic fibres (see Annex F).
    separating excess metal (feeders, risers, gates and sprues; by sawing,
    flame- or compressed air-cutting, and/or grinding). During the fettling   2.3 Physicochemical properties
    process, the iron or steel casting may undergo a heat treatment and       Since the emission of iron and steel founding is a complex mixture of
    primer painting.                                                          gases, aerosols and particles, no physicochemical properties are
                                                                              specified.
 2.2 Composition of the iron and steel founding emissions
 As is described in the previous section, the iron and steel foundry industry
 is very diverse in materials and processes. This results in occupational
 exposures to a wide variety of substances (gases, aerosols and particles),
 some likely involving almost all workers, some only concerning specific
 job titles or working areas in the foundry. Substances that can be found in
12        Health Council of the Netherlands | No. 2020/02                                                               2                                14
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<pre> chapter 03 | International classification             Iron and steel founding emissions | page 14 of 87
 03
 international
 classification
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<pre> chapter 03 | International classification                                   Iron and steel founding emissions | page 15 of 87
 3.1 European Commission
 Not evaluated.
 3.2 IARC
 In 2012, the Working Group of IARC summarized that there is sufficient
 evidence in humans for the carcinogenicity of occupational exposures
 during iron and steel founding.7 Occupational exposures during iron and
 steel founding cause cancer of the lung. No data on the carcinogenicity to
 experimental animals of mixtures present in iron and steel founding were
 available to the Working Group. Overall, IARC concluded that
 occupational exposures during iron and steel founding are carcinogenic to
 humans (Group 1). A summary of the evaluation and conclusion by IARC
 is given in Annex A. Annex G shows a list of individual components, which
 can most likely be found in the emission of iron and steel founding, and
 which are classified by IARC.
 3.3 The Health Council of the Netherlands
 Not evaluated. Annex G shows a list of individual components, which can
 most likely be found in the emissions of iron and steel founding, and which
 are officially classified in the Netherlands.
14       Health Council of the Netherlands | No. 2020/02                                    2                                16
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<pre> chapter 04 | Monitoring                               Iron and steel founding emissions | page 16 of 87
 04
 monitoring
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<pre> chapter 04 | Monitoring                                                    Iron and steel founding emissions | page 17 of 87
 4.1 Environmental exposure monitoring
 Exposure to the iron and steel founding emissions implies exposure to a
 complex mixture, suggesting that varying markers may be applied for the
 measurement of exposure in workplaces. Overall, in the literature no
 preference for a certain exposure marker is identified. However, in human
 studies on the carcinogenic potential of occupational exposure during iron
 and steel founding, airborne concentrations of respirable dust and quartz,
 carbon monoxide, binder compounds, polycyclic aromatic hydrocarbons,
 metals, and refractory ceramic fibers have been used to assess exposure
 to the emission of iron and steel founding.
 4.2 Biological exposure monitoring
 Not specified.
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<pre> chapter 05 | Manufacture and uses                     Iron and steel founding emissions | page 18 of 87
 05
 manufacture
 and uses
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<pre> chapter 05 | Manufacture and uses                                           Iron and steel founding emissions | page 19 of 87
 5.1 Manufacture
 The emissions are unintentionally formed during iron and steel founding
 operations.
 5.2 Identified uses
 Iron and steel founding is used to produce a large variety of semi-finished
 and finished metal products for a wide range of construction and
 engineering applications, such as machine and motor parts, cookware,
 pipes, pumps, valves, nails, and ship paddles.
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<pre> chapter 06 | Summary of (toxico)kinetics              Iron and steel founding emissions | page 20 of 87
 06
 summary of
 (toxico)kinetics
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<pre> chapter 06 | Summary of (toxico)kinetics                                 Iron and steel founding emissions | page 21 of 87
 Data on absorption, distribution, elimination, and toxicokinetics are
 available for certain individual substances that can be found in the
 emissions of iron and steel founding, but no such data are available for
 the emission as a whole. Since in the present report the individual
 substances in the emissions are not evaluated, this topic is not further
 discussed.
20      Health Council of the Netherlands | No. 2020/02                                  2                                22
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<pre> chapter 07 | Germ cell mutagenicity                   Iron and steel founding emissions | page 22 of 87
 07
 germ cell
 mutagenicity
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<pre> chapter 07 | Germ cell mutagenicity                                                                                            Iron and steel founding emissions | page 23 of 87
 7.1 Summary and relevance of the provided information on                                         Clastogenic and aneugenic effects
        (germ cell) mutagenicity                                                                  Humfrey et al. (1996) tested whether fume extracts from binder system
                                                                                                  sites in an iron foundry, could induce micronuclei in a human
 7.1.1 Summary of genotoxicity tests in vitro                                                     lymphoblastoid cell line.8 As shown in Table 1, the extracts increased the
                                                                                                  number of cells with micronuclei in a dose-dependent matter. No other
 Mutagenicity                                                                                     studies are available.
 The results of the mutagenicity tests are shown in Annex H. Three studies
 were considered sufficiently reliable. In these studies, samples of aerosols                     Unscheduled DNA synthesis
 and fumes, which are formed during iron and steel founding, and obtained                         Humfrey et al. (1996) also reported that the fume extracts induced
 from several plants in various countries, induced reverse mutations in                           unscheduled DNA synthesis in a dose-dependent matter (see Table 2).8
 Salmonella typhimurium strains TA98 and TA100.                                                   No other studies are available.
 Table 1. Micronuclei formation
  Method and reference          Cell type and conditions            Source test substance and doses applied in test    Results                                            Reliability (Annex B)
                                                                    system
  Micronucleus test             MCL-5 cells (human lymphoblastoid   Iron foundry fumes sampled from 3 different binder Statistically significant dose-related increase in Reliability 2
                                cell line)                          systems (in casting area):                         number of micronucleated cells/500 binuclear
  Humfrey et al. (1996)8                                            -	A: green sand binder                            cells reported
                                500 binucleated cells per dose      -	B: shellmould binder
                                applied were scored for micronuclei -	C: cold box amine gassed binder                 Significant cytotoxicity observed at highest dose
                                                                                                                       applied (based on cut-off of 20% decrease in
                                                                    Final concentration of fume suspension applied:    viability)
                                                                    0, 1, 5 and 10 μg/ml
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<pre> chapter 07 | Germ cell mutagenicity                                                                                                   Iron and steel founding emissions | page 24 of 87
 Table 2. Unscheduled DNA synthesis.
  Method and reference         Cell type and conditions              Source test substance and doses applied in       Results                                                 Reliability (Annex B)
                                                                     test system
  Unscheduled DNA synthesis    Primary rabbit tracheal cells and rat Iron foundry fumes sampled from 3 different      Rabbit tracheal cells                                   Well-performed study
                               hepatocytes                           binder systems (in casting area):                Statistically significant dose-related increase in net
  Humfrey et al. (1996)8                                             -	A: green sand binder                          nuclear grains reported                                 Reliability 1
                                                                     -	B: shellmould binder                          Rat hepatocytes
                                                                     -	C: cold box amine gassed binder               Statistically significant dose-related increase in net
                                                                                                                      nuclear grains reported
                                                                     Concentration of fume suspension applied:
                                                                     - Rabbit cells: 0, 100, 500 and 1,000 μg/ml     Overall, fumes suspensions from various binder
                                                                     - rat cells: 0, 50, 100, 200 and 500 μg/ml      systems showed differences in potency, the lowest
                                                                                                                      potency found in binder C.
                                                                     Positive control rabbit cells: 1,6-dinitropyrene
                                                                     Positive control rat cells: 2-acetylaminoflurene Significant cytotoxicity noted at or above 500 μg/ml in
                                                                                                                      rabbit tracheal cells; no toxicity observed in rat
                                                                                                                      hepatocytes
 Conclusion on genotoxicity                                                                           studies the concentration of benzo(a)pyrene, a well-known mutagenic and
 The committee remarks that the number of studies on in vitro genotoxicity                            carcinogenic substance, served as exposure marker to the emission of
 (other than mutagenicity tests) is limited, and that the study on                                    iron and steel founding.
 unscheduled DNA synthesis does not give evidence of genotoxicity, but                                In a single study, no increased mutations were found in the hypoxanthine-
 rather is a marker for exposure that supports the suggestion of                                      guanine phosphoribosyl transferase (HPRT) gene in white blood cells with
 genotoxicity. However, it is clear to the committee that extracts of the iron                        and without adjustment for smoking habits.
 and steel founding emissions induce gene mutations in vitro.                                         In another single study, no difference was observed in the frequency of
                                                                                                      micronuclei in white blood cells between workers exposed to high and low
 7.1.2 Summary of human data relevant for germ cell mutagenicity                                      concentrations of benzo(a)pyrene (high, 3.1-13.7 µg/m3; low, 0.0-0.006
 Data on gene mutations, other genotoxic effects and effects on DNA are                               µg/m3).9 Two other studies on chromosome aberrations and sister
 summarized in Annex I. The small studies have been performed with iron                               chromatid exchanges could not be interpreted by the committee due to
 and steel foundry workers from which blood samples were taken. In the                                low quality.
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<pre> chapter 07 | Germ cell mutagenicity                                                                   Iron and steel founding emissions | page 25 of 87
 In four studies, moderate to clear increases in DNA-adduct formation       Extracts from the emissions of iron and steel founding showed to be
 were observed, but in only two studies the increase reached statistical    mutagenic in in vitro test systems. Additional information in two of the
 significance. However, since DNA-adduct formation is more an indication    three mutagenicity studies showed that in these extracts benzo(a)pyrene
 of exposure rather than an indication for genotoxicity, these data are not or coal tar pitch was present, two substances, which are well known to
 further evaluated.                                                         have carcinogenic and mutagenic potential. Limited evidence is available
 Overall, the number of studies on human materials obtained from foundry    on the clastogenic properties of extracts of the emissions of iron and steel
 workers is very limited, and those with sufficient quality do not show     founding (in vitro and in vivo tests). To the opinion of the Committee,
 mutagenic or clastogenic activity.                                         all these findings indicate that a classification in category 2 (“cause of
                                                                            concern for humans owing to the possibility that it may induce heritable
 7.1.2 Summary of genotoxicity tests in mammalian somatic                   mutations in the germ cells of humans”) is warranted.
         or germ cells in vivo
 Currently, no animal experiments have been performed on the genotoxic      7.3 Recommendation on the classification for
 activity of the emissions samples of iron and steel founding.                     germ cell mutagenicity
                                                                            Based on the available data, the Committee recommends classifying iron
 7.2 Evaluation of the germ cell mutagenicity                               and steel founding emissions as a germ cell mutagen in category 2
 No data have been found on germ cell mutagenicity in humans or             (“Cause of concern for humans owing to the possibility that they may
 mammals. In addition, no genotoxicity tests in germ cells have been        induce heritable mutations in the germ cells of humans”).
 performed with samples taken from iron and steel founding emissions.
 Therefore, the committee concludes that there is a lack of evidence
 to classify iron and steel founding emissions in category 1 (“known to
 induce heritable mutations in the germ cells of humans”).
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<pre> chapter 08 | Carcinogenicity                          Iron and steel founding emissions | page 26 of 87
 08
 carcinogenicity
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<pre> chapter 08 | Carcinogenicity                                                                            Iron and steel founding emissions | page 27 of 87
 8.1 Summary and relevance of the provided information on                    in a conference abstract only.13 Therefore this study will not be further
       carcinogenicity                                                       discussed by the committee.
                                                                             Notes by the committee. In the meta-analyses by Rota et al. and Bosetti
 8.1.1 Observations in humans                                                et al., the authors reported the presence of heterogeneity between the
 Available data on cancer development in humans are summarized in            studies. This is not surprising to the committee, because the exposure in
 Annex J (meta-analyses), K (cohort studies), and L (case-control studies).  the iron and steel foundries vary considerably among each other. In most
 The publications contain data from studies of industrial workers worldwide, cohort studies data on smoking habits or other potentially confounding
 which are exposed to the emissions of iron and steel founding at varying    factors were not collected or reported, and therefore were not taken into
 exposure levels, and under various exposure circumstances.                  account in the meta-analyses.
                                                                             Overall, the meta-analyses demonstrate a 30% excess risk for cancer of
 Meta-analyses                                                               the lung in iron and steel foundry industries, and no excess risk for
 Four meta-analyses have been published on occupational exposure             hematopoietic cancers. The potential impact of unmeasured confounding
 during iron and steel founding. Rota et al. (2014) used data from           factors cannot be fully excluded.
 13 cohort studies, which is an update from Bosetti et al. (2006).10,11
 They associated occupational exposure during iron and steel founding        Cohort studies
 with increased cancer mortality in the lungs (pooled relative risk (RR)     Twenty-five retrospective cohort studies have been performed on cancer
 1.31, 95% confidence interval (95%CI) 1.07-1.61), larynx (pooled RR         mortality among iron and steel workers, of which five studies were not
 1.48, 95%CI 1.14-1.91) and bladder (pooled RR 1.38, 95%CI 1.14-1.91).10     considered by the committee due to low quality. Overall, in fifteen of the
 Alicandro et al. (2016) did not find an association for lymphatic and       twenty studies a positive association with statistical significance have
 haematopoietic neoplasms; data on possible neoplasms or cancer at           been found between occupational exposure to the iron and steel founding
 other sites of the body were not analysed.12 Singh et al. (2018) focused on emissions and certain types of cancer, such as lung, stomach and bladder
 PAH exposure-associated lung cancer and therefore included only three       cancer. In five studies (limited) data on smoking habits were available;
 studies (two were also included in Rota et al. (2014), one was described    in three of these studies, the association was still positive when data were
                                                                             adjusted for these smoking habits, or after indicating that there was no
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<pre> chapter 08 | Carcinogenicity                                                                            Iron and steel founding emissions | page 28 of 87
 difference in percentage of smokers between exposed and reference            cancer mortality.18 The committee noted that for accurate exposure levels
 group.                                                                       in relation to cancer development, also historical exposure levels should
 In fifteen studies data on exposure-response relationships were              be taken into account, since working conditions may change over time.
 presented, using years of employment, job title, employment history, or      In a nested-case control study, Moulin et al. (2000) observed increased
 age, as indicators for cumulative exposure. For instance, Adzersen et al.    trends between estimated PAH exposure and lung cancer mortality
 (2003) found increased lung cancer mortality among workers with more         (odds ratio 1.42, p=0.06).19 The estimated PAH exposures were based
 than 30 years of exposure since first exposure compared to workers with      on exposure levels that might have occurred in the past, and thus may
 less than 10 years of exposure since first exposure (standardized mortality  contain a degree of uncertainty.
 ratio (SMR), 1.36, 95% confidence interval 1.04-1.99).14 In the small study  Notes by the committee. Various factors may have influenced the
 by Mallin et al. (1998), an association between bladder cancer mortality     outcomes of the cohort studies. These include variations in working
 and heaters was reported, but no associations were found for other job       conditions and thus in exposure levels and composition, uncertainties in
 titles.15 Sitas et al. (1989) found a positive association between lung      historical exposure, not accounting for smoking habits, and lack of data on
 cancer mortality in workers of 65 years old or older, but not in the younger latency. However, the majority of the retrospective cohort studies showed
 population.16 In addition, Westberg et al. (2013) reported a positive        an association between exposure to iron and steel foundry emissions and
 association between a latency period (period between exposure and            increased cancer development.
 cancer development) of more than 20 years and lung cancer mortality,
 irrespective of the duration of employment (0-19 years of employment,        Case-control studies
 SMR, 2.35 (95% confidence interval 1.12-4.32); more than 20 years of         Seven case-control studies were available on workers population. Overall
 employment, SMR, 1.72 (95% confidence interval 1.08-2.61).17                 workers’ exposure is assessed by job titles, work areas and duration of
 However, in the majority of the cohort studies no associations have been     employment, rather than by measuring exposure levels. Statistically
 found between duration of tenure in the iron and steel founding industry,    significant positive associations were found for lung cancer, and in one
 and cancer mortality.                                                        study also for stomach cancer.20-24 In five studies data were adjusted for
 In two studies, the level of PAH exposure was assessed. Tola et al. (1979)   tobacco smoking. In the study by Becher et al. (1989), a positive
 found no clear association between current PAH exposure and lung             association was only found among iron and steel workers with the longest
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<pre> chapter 08 | Carcinogenicity                                                                            Iron and steel founding emissions | page 29 of 87
 years of employment (more than 30 years),20 whereas Xu et al. (1996)        risk among iron and steel founding workers. Therefore, the Committee
 found positive associations in groups of workers with less than 15 years    does not preclude beforehand the studies with no or insufficient data on
 of employment.23 In two population-based studies no associations were       smoking habits for the hazard assessment, unless it is clear that the
 found for lung cancer or bladder cancer and working in iron and steel       reference population is not comparable with the exposed population.
 foundries.25,26                                                             This may also account for co-morbidities. The ‘healthy worker’ effect may
 Notes by the committee. No data were reported on historical and current     have resulted in an underestimation of work-related cancer cases in
 exposure to substances in the emission of iron and steel founding.          retrospective and case-control studies to some degree. However, it is
 In addition, possible confounding by the healthy worker effect was not      reasonable to assume that this phenomenon has only a minor influence
 taken into account, indicating that the calculated excess of cancer         on the number of cancer cases, because cancer development may take
 mortality could be underestimated. Overall, taking into account these       many years before complaints start to occur, whereas complaints are a
 notes, in case-control studies associations were found between exposure     reason for a worker to leave the workplace early. Therefore exclusion of
 to iron and steel foundry emissions and increased cancer development.       the these types of studies for the hazard assessment is not necessary.
 Conclusion on observations in humans                                        Overall and taking into account potential bias and confounding, the
 Occupational exposure to the emissions of iron and steel founding           majority of the cohort studies showed an association between exposure
 comprises exposure to a complex mixture of substances with variable         to the emissions of iron and steel founding and increased cancer mortality,
 composition and concentrations, indicating some degree of heterogeneity.    in particular lung cancer mortality. The case-control studies support the
 In addition, not always potential bias or confounding was taken into        findings from the cohort studies. In conclusion, the committee is of the
 account, such as smoking habits and the healthy worker effect.              opinion that there is sufficient evidence of an association between
 Smoking is strongly associated with lung and bladder cancer, and thus       occupational exposure to iron and steel founding emissions of and
 may have influenced the outcome of the cohort studies if smoking rates      increased lung cancer development in humans.
 between the iron and steel founding workers differed from the reference
 population. Three cohort studies explored this issue and demonstrated
 that it is unlikely that smoking behavior fully explained the excess cancer
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<pre> chapter 08 | Carcinogenicity                                                                             Iron and steel founding emissions | page 30 of 87
 8.1.2 Animal carcinogenicity studies                                         steel founding and lung cancer development in humans. According to the
 Humfrey et al. (1996) performed an animal experiment on the                  criteria, the exposure should be considered as “known to be carcinogenic
 carcinogenicity of extracts of aerosols collected from the emissions of iron to humans”, which corresponds to classification in category 1A.
 and steel founding.8 Male and female Wistar rats (N=50 animals/sex/
 group) were exposed to iron foundry fume extracts in pellets by              Genotoxicity data from in vitro test systems show that extracts from the
 intrabroncheal installation in a two-year rodent bioassay. The authors did   emissions of iron and steel founding induced mutations. This suggests
 not find tumours that could be related to fume extract exposure, although    that the emissions likely cause cancer by a stochastic genotoxic mode of
 preneoplastic lesions in the bronchial epithelium were observed in treated   action. A further indication that this type of carcinogenic mechanism may
 animals when compared to control animals. The committee noted that the       play a role comes from two of the three mutagenicity studies using the
 chosen exposure route is irrelevant for the human working situation.         reverse mutation assay, in which benzo(a)pyrene or coal tar pitch were
 Furthermore, reporting on tumour development was limited (no data on         detected in the test samples. These substances are well known for their
 general toxicity, body weight gain, food consumption, etc.). Therefore, the  mutagenic activity.
 committee considers this study too limited for a conclusion. So far known,
 no other animal experiments have been performed.                             8.3 Recommendation on the classification for carcinogenicity
                                                                              The committee concludes that the iron and steel founding emissions are
 8.2 Evaluation of the carcinogenicity                                        carcinogenic to humans, and recommends classifying the exposure in
 Several observational studies among workers in the iron and steel foundry    category 1A (“known to have carcinogenic potential for humans”).
 industry show a positive association between exposure to the emissions
 of iron and steel founding and cancer-related mortality. Types of cancer     In addition, the committee concludes that the emissions are likely to cause
 observed include mainly lung cancer, but also bladder and stomach            cancer by a stochastic genotoxic mode of action.
 cancer have been reported. Data on animal carcinogenicity is too limited
 to draw a conclusion. Based on the observational studies, and taking into
 account bias and confounding, the Committee concludes that there is
 sufficient evidence for an association between exposure during iron and
29       Health Council of the Netherlands | No. 2020/02                                                                 2                                31
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<pre> chapter 08 | References                               Iron and steel founding emissions | page 31 of 87
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                                                                                Decoufle P and Wood D. Mortality patterns among workers in a gray
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    Koskela RS. Mortality, morbidity and health selection among metal           iron foundry. Am J Epidemiol 1979; 109: 667-75.
    workers. Scand J Work Environ Health 1997; 23 Suppl 2: 1-80.             63
                                                                                Breslin P. Mortality among foundry men in steel mills. Editor: Lemen R,
 54
    Sherson D, Svane O and Lynge E. Cancer incidence among foundry              Dement, JM (eds). Dusts and Disease: IL: Pathotox Publishers, 1979;
    workers in Denmark. Arch Environ Health 1991; 46(2): 75-81.                 pages 439-447;
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<pre> chapter 08 | References                                                     Iron and steel founding emissions | page 36 of 87
 64
    Egan-Baum E, Miller B and Waxweiler R. Lung cancer and other
    mortality patterns among foundrymen. Scand J Work Environ Health
    1981; 7: 147-55.
 65
    Oddone E, Scaburri A, Bai E, Modonesi C, Stracci F, Marchionna G, et
    al. Occupational brain cancer risks in Umbria (Italy), with a particular
    focus on steel foundry workers. G Ital Med Lav Erg 2014; 36: 111-7.
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<pre> Annexes                                              Iron and steel founding emissions | page 37 of 87
 annexes
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<pre> Annexes                                                                                                   Iron and steel founding emissions | page 38 of 87
 A        IARC evaluation and                                                   significant excess of lung cancer in association with foundry work, with
                                                                                adjustment for smoking. Considering the observations in the cohort
          conclusion                                                            studies and case-control studies, the epidemiological data clearly support
                                                                                the notion that work in iron and steel foundries is associated with an
                                                                                increased risk for lung cancer. Chance, bias and confounding are not
 Iron and steel founding was considered by IARC Working Groups in 1984,         likely to explain the excess risk.
 1987 and in 2012.5-7 Foundries produce shaped castings from re-melted
 metal ingots and scrap. The processes in iron and steel founding               There are no data available on cancer in experimental animals.
 generally comprise pattern-making, moulding and core-making, melting,
 pouring and shake-out, and fettling. A detailed description of these           Exposures in the iron and steel founding industry are complex and
 production steps can be found in IARC (1984).5 The iron and steel industry     includes a wide variety of known genotoxic and carcinogenic substances
 is very diverse in materials and processes, resulting in occupational          including PAHs, metals (e.g. nickel, chromium) and formaldehyde. These
 exposures to a wide variety of substances, including (but not limited to)      agents have been previously reviewed by IARC (1983, 1990, 1995, 2010).
 silica and carbon monoxide, airborne polycyclic aromatic hydrocarbons          In human studies a (significant) correlation was observed between the
 (PAHs), airborne chromium and nickel compounds, phenol, formaldehyde,          estimated exposures and DNA-adduct levels in peripheral white blood
 isocyanates and various amines. In several studies significant exposure        cells or in leucocytes. Based on this it was concluded that there is
 levels of one or more of these substances were demonstrated.                   moderate evidence that extracts of particles collected from a steel foundry
                                                                                act through a genotoxic mechanism, based on bacterial mutation studies.
 There were 13 cohort studies available on iron and steel founding              There is weak evidence of a genotoxic mechanism of action for exposure
 workers in various parts of the world. A significantly increased risk for lung during iron and steel founding, based on DNA-adduct studies.
 cancer was observed in almost all cohorts or high-exposed subgroups.
 In two additional cohorts supportive evidence of an excess of lung cancer      Based on the available information, IARC concluded that there is sufficient
 in foundry workers was observed, based on proportional mortality.              evidence in human for carcinogenicity of occupational exposures during
 Two population-based case-control studies demonstrated a statistically
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<pre> Annexes                                                                   Iron and steel founding emissions | page 39 of 87
 iron and steel founding. Occupational exposures during iron and steel
 founding cause cancer of the lung.
 No data on the carcinogenicity to experimental animals of mixtures
 present in iron and steel founding were available to the Working Group.
 Occupational exposures during iron and steel founding are carcinogenic to
 humans (Group 1).
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<pre> Annexes                                                                                                     Iron and steel founding emissions | page 40 of 87
 B          reliability testing of animal and                                     Reliability 4 (not assignable)
                                                                                  For example, only short abstract available; only secondary literature
            in vitro studies                                                      (review, tables, books, etc.).
 To assess the reliability of animal and in vitro studies, the Committee uses
 the criteria set by Klimisch et al. 1997.1 A summary of the criteria of the
 reliability scores is given below. Only studies with a reliability score of 1 or
 2 are considered in assessing genotoxicity and carcinogenicity.
 Reliability 1 (reliable without restriction)
 For example, guideline study (OECD, etc.); comparable to guideline study;
 test procedure according to national standards (DIN, etc.).
 Reliability 2 (reliable with restrictions)
 For example, acceptable, well-documented publication/study report
 which meets basic scientific principles; basic data given: comparable to
 guidelines/standards; comparable to guideline study with acceptable
 restrictions.
 Reliability 3 (not reliable)
 For example, method not validated; documentation insufficient for
 assessment; does not meet important criteria of today standard methods;
 relevant methodological deficiencies; unsuitable test system.
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<pre> Annexes                                                                                                Iron and steel founding emissions | page 41 of 87
 C reliability testing of                                                   (5)   The sample/exposure range was sufficient to study the question
                                                                                  under investigation, so that effects estimates are not constrained by
           epidemiological studies                                                high imprecision.
                                                                            (6)	The data were analysed using appropriate statistical techniques
                                                                                   to address the research questions and model assumptions.
 To assess the reliability of epidemiological studies, the Committee uses   (7)	The methodology and results were comprehensively and
 the criteria set by Money et al.(2013).2 A summary of the reliability            transparently reported according to relevant guidelines (e.g., the
 categories set by Money et al. (2013) is given below. Only studies with          STROBE guidelines for observational data, Von Elm et al. 2007).27
 a reliability score of 1 or 2 are considered in assessing genotoxicity and
 carcinogenicity.                                                           Acute or specific outcomes
                                                                            The same principles should be applied as for chronic, non-specific
 Reliability 1 (reliable without restriction)                               outcomes. The focus lies more with how well exposure has been
 Chronic, non-specific outcomes                                             characterised, and the disease outcome is defined.
 Appropriate study design to research question.
 (1)	Selected subjects or persons at risk represent appropriate exposure   Reliability 2 (reliable with restrictions)
       distributions. Adequate procedures of follow-up and reduction        Chronic, non-specific outcomes
       of loss to follow up were performed.                                 Applies to studies which possess most of the qualities of studies with
 (2)	Exposure assessment was made independent of outcome with              reliability 1. The overall quality is comprised due to minor, but obvious,
       validated methods, preferentially with individual exposure data.     methodological limitations. Examples include well-designed and
 (3)	Effect data were collected independently from exposure status,        conducted studies, but with limited measurement data, possibility of some
       using standardized data collection procedures/registries.            residual confounding, some imprecision due to small sample size or low
 (4)	The possibility of serious bias has been reduced by design,           exposure range.
       controlled through statistical adjustment, and/or quantified through
       sensitivity analyses.
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<pre> Annexes                                                                  Iron and steel founding emissions | page 42 of 87
 Acute or specific outcomes
 The same principles should be applied as for chronic, non-specific
 outcomes. Examples of shortcomings may include a lack of individual
 exposure data, and effects derived from self-reported outcomes.
 Note: some studies with serious methodological limitations may provide
 reliable information for an acute or specific outcome.
 Reliability 3 (not reliable)
 The studies fail to meet one or more of the most basic standards
 necessary to interpret epidemiologic research, such as appropriate study
 design to the research question. Shortcomings may include using census
 job titles as a surrogate for exposure.
 Reliability 4 (not assignable)
 This includes studies or data which do not give sufficient details about
 methodology used, or which are short listed in abstracts or secondary
 literature.
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<pre> Annexes                                                                                              Iron and steel founding emissions | page 43 of 87
 D classification on germ cell                                            non-physiological manner (temporarily) alter its replication. Genotoxicity
                                                                          test results are usually taken as indicators for mutagenic effects.
           mutagenicity
                                                                          3.5.2. Classification criteria for substances
 Source: Section 3.5 (Germ cell mutagenicity) of Regulation No. 1272/2008 3.5.2.1. This hazard class is primarily concerned with substances that may
 of the European Parliament and of the council of 10 August 2009 on       cause mutations in the germ cells of humans that can be transmitted to
 classification, labelling and packaging of substances.3                  the progeny. However, the results from mutagenicity or genotoxicity tests
                                                                          in vitro and in mammalian somatic and germ cells in vivo are also
 3.5.1. Definitions and general considerations                            considered in classifying substances and mixtures within this hazard
                                                                          class.
 3.5.1.1. A mutation means a permanent change in the amount or structure
 of the genetic material in a cell. The term ‘mutation’ applies both to   3.5.2.2. For the purpose of classification for germ cell mutagenicity,
 heritable genetic changes that may be manifested at the phenotypic level substances are allocated to one of two categories as shown in
 and to the underlying DNA modifications when known (including specific   Table 3.5.1.
 base pair changes and chromosomal translocations). The term
 ‘mutagenic’ and ‘mutagen’ will be used for agents giving rise to an      3.5.2.3 Specific considerations for classification of substances as germ
 increased occurrence of mutations in populations of cells and/or         cell mutagens
 organisms.
                                                                          3.5.2.3.1. To arrive at a classification, test results are considered from
 3.5.1.2. The more general terms ‘genotoxic’ and ‘genotoxicity’ apply to  experiments determining mutagenic and/or genotoxic effects in germ and/
 agents or processes which alter the structure, information content, or   or somatic cells of exposed animals. Mutagenic and/or genotoxic effects
 segregation of DNA, including those which cause DNA damage by            determined in in vitro tests shall also be considered.
 interfering with normal replication processes, or which in a
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<pre> Annexes                                                                                                                                     Iron and steel founding emissions | page 44 of 87
                                                                                                            Categories   Criteria
 3.5.2.3.2. The system is hazard based, classifying substances on the                                       CATEGORY 2:  Substances which cause concern for humans owing to the possibility that they may
                                                                                                                         induce heritable mutations in the germ cells of humans. The classification in
 basis of their intrinsic ability to induce mutations in germ cells.                                                     Category 2 is based on:
 The scheme is, therefore, not meant for the (quantitative) risk assessment                                              -	positive evidence obtained from experiments in mammals and/or in some cases
                                                                                                                            from in vitro experiments, obtained from:
 of substances.                                                                                                             - somatic cell mutagenicity tests in vivo, in mammals; or
                                                                                                                            -	other in vivo somatic cell genotoxicity tests which are supported by positive
                                                                                                                               results from in vitro mutagenicity assays.
 Table 3.5.1 Hazard categories for germ cell mutagens                                                                    Note: Substances which are positive in in vitro mammalian mutagenicity assays, and
                                                                                                                         which also show chemical structure activity relationship to known germ cell
  Categories    Criteria                                                                                                 mutagens, shall be considered for classification as Category 2 mutagens.
  CATEGORY 1:   Substances known to induce heritable mutations or to be regarded as if they induce
                heritable mutations in the germ cells of humans. Substances known to induce
                heritable mutations in the germ cells of humans.                                           3.5.2.3.3. Classification for heritable effects in human germ cells is made
  Category 1A:  The classification in Category 1A is based on positive evidence from human
                                                                                                           on the basis of well conducted, sufficiently validated tests, preferably as
                epidemiological studies. Substances to be regarded as if they induce heritable
                mutations in the germ cells of humans.                                                     described in Regulation (EC) No 440/2008 adopted in accordance with
  Category 1B:  The classification in Category 1B is based on:                                             Article 13(3) of Regulation (EC) No 1907/2006 (‘Test Method Regulation’)
                -	positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or
                -	positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in          such as those listed in the following paragraphs. Evaluation of the test
                   combination with some evidence that the substance has potential to cause
                   mutations to germ cells. It is possible to derive this supporting evidence from         results shall be done using expert judgement and all the available
                   mutagenicity/ genotoxicity tests in germ cells in vivo, or by demonstrating the ability
                                                                                                           evidence shall be weighed in arriving at a classification.
                   of the substance or its metabolite(s) to interact with the genetic material of germ
                   cells; or
                -	positive results from tests showing mutagenic effects in the germ cells of humans,
                   without demonstration of transmission to progeny; for example, an increase in the       3.5.2.3.4. In vivo heritable germ cell mutagenicity tests, such as:
                   frequency of aneuploidy in sperm cells of exposed people.
                                                                                                           — rodent dominant lethal mutation test;
                                                                                                           — mouse heritable translocation assay.
                                                                                                           3.5.2.3.5. In vivo somatic cell mutagenicity tests, such as:
                                                                                                           — mammalian bone marrow chromosome aberration test;
                                                                                                           — mouse spot test;
                                                                                                           — mammalian erythrocyte micronucleus test.
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<pre> Annexes                                                                                                    Iron and steel founding emissions | page 45 of 87
 3.5.2.3.6. Mutagenicity/genotoxicity tests in germ cells, such as:          exposure used in the study of the substance compared to the route of
 (a)	mutagenicity tests:                                                    human exposure shall also be taken into account.
       mammalian spermatogonial chromosome aberration test;
       spermatid micronucleus assay;                                         3.5.3 Classification criteria for mixtures
 (b)	Genotoxicity tests:
       sister chromatid exchange analysis in spermatogonia;                  3.5.3.1. Classification of mixtures when data are available for all
       nscheduled DNA synthesis test (UDS) in testicular cells.              ingredients or only for some ingredients of the mixture
 3.5.2.3.7. Genotoxicity tests in somatic cells such as:                     3.5.3.1.1. The mixture shall be classified as a mutagen when at least
 — liver Unscheduled synthesis test (UDS) in vivo;                           one ingredient has been classified as a Category 1A, Category 1B or
 — mammalian bone marrow Sister Chromatid Exchanges (SCE);                   Category 2 mutagen and is present at or above the appropriate generic
                                                                             concentration limit as shown in Table 3.5.2 for Category 1A, Category 1B
 3.5.2.3.8. In vitro mutagenicity tests such as:                             and Category 2 respectively.
 — in vitro mammalian chromosome aberration test;
                                                                             Table 3.5.2 Generic concentration limits of ingredients of a mixture classified as germ
 — in vitro mammalian cell gene mutation test;
                                                                             cell mutagens that trigger classification of the mixture.
 — bacterial reverse mutation tests.
                                                                              Ingredient classified Concentration limits triggering classification of a mixture as:
                                                                              as:                   Category 1A            Category 1B             Category 2 mutagen
                                                                                                    mutagen                mutagen
 3.5.2.3.9. The classification of individual substances shall be based on
                                                                              Category 1A mutagen   ≥ 0,1%                 -                       -
 the total weight of evidence available, using expert judgement (See 1.1.1).  Category 1B mutagen   -                      ≥ 0,1%                  -
 In those instances where a single well-conducted test is used for            Category 2 mutagen    -                      -                       ≥ 1,0%
 classification, it shall provide clear and unambiguously positive results.
 If new, well validated, tests arise these may also be used in the total     Note. The concentration limits in the table above apply to solids and liquids (w/w units)
 weight of evidence to be considered. The relevance of the route of          as well as gases (v/v units).
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<pre> Annexes                                                                                                   Iron and steel founding emissions | page 46 of 87
 3.5.3.2. Classification of mixtures when data are available for the           data shall be used in accordance with the applicable bridging rules set
 complete mixture                                                              out in section 1.1.3.
 3.5.3.2.1. Classification of mixtures will be based on the available test     3.5.4. Hazard communication
 data for the individual ingredients of the mixture using concentration limits
 for the ingredients classified as germ cell mutagens. On a case-by-case       3.5.4.1. Label elements shall be used in accordance with Table 3.5.3,
 basis, test data on mixtures may be used for classification when              for substances or mixtures meeting the criteria for classification in this
 demonstrating effects that have not been established                          hazard class.
                                                                               Table 3.5.3 Label elements of germ cell mutagenicity
 from the evaluation based on the individual ingredients. In such cases,
                                                                                Classification              Category 1A or Category 1B        Category 2
 the test results for the mixture as a whole must be shown to be conclusive
                                                                                GHS Pictograms
 taking into account dose and other factors such as duration, observations,
 sensitivity and statistical analysis of germ cell mutagenicity test systems.
                                                                                Signal word                 Danger                            Warning
 Adequate documentation supporting the classification shall be retained
                                                                                Hazard Statement            H340: May cause genetic           H341: Suspected of causing
 and made available for review upon request.                                                                defects (state route of exposure  genetic defects (state route of
                                                                                                            if it is conclusively proven that exposure if it is conclusively
                                                                                                            no other routes of exposure       proven that no other routes of
 3.5.3.3 Classification of mixtures when data are not available for the                                     cause the hazard)                 exposure cause the hazard)
 complete mixture: bridging principles                                          Precautionary Statement     P201, P202, P281                  P201, P202, P281
                                                                                Prevention
                                                                                Precautionary Statement     P308 + P313                       P308 + P313
 3.5.3.3.1. Where the mixture itself has not been tested to determine its       Response
 germ cell mutagenicity hazard, but there are sufficient data on the            Precautionary Statement     P405                              P405
                                                                                Storage
 individual ingredients and similar tested mixtures (subject to paragraph       Precautionary Statement     P501                              P501
 3.5.3.2.1), to adequately characterise the hazards of the mixture, these       Disposal
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<pre> Annexes                                                                   Iron and steel founding emissions | page 47 of 87
 3.5.5. Additional classification considerations
 It is increasingly accepted that the process of chemical-induced
 tumorigenesis in humans and animals involves genetic changes for
 example in proto-oncogenes and/or tumour suppresser genes of somatic
 cells. Therefore, the demonstration of mutagenic properties of substances
 in somatic and/or germ cells of mammals in vivo may have implications
 for the potential classification of these substances as carcinogens
 (see also Carcinogenicity, section 3.6, paragraph 3.6.2.2.6).
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<pre> Annexes                                                                                                     Iron and steel founding emissions | page 48 of 87
 E        classification on carcinogenicity                                   Category Judgement of the Committee (GRGHS)                               Comparable with EU
                                                                                                                                                        Category
                                                                              1A       The compound is known to be carcinogenic to humans.              1A
                                                                                       It acts by a stochastic genotoxic mechanism.
                                                                                       It acts by a non-stochastic genotoxic mechanism.
 In 2010, the committee published a guideline for classifying substances in            It acts by a non-genotoxic mechanism.
                                                                                       Its potential genotoxicity has been insufficiently investigated.
 terms of their carcinogenic properties, and for assessing their
                                                                                       Therefore, it is unclear whether the compound is genotoxic.
 genotoxicity.4 The classification on carcinogenic properties is based on the
 Globally Harmonized System which is also used by the European Union          1B       The compound is presumed to be as carcinogenic to                1B
                                                                                       humans.
 for the classification, labelling and packaging of substances and mixtures            It acts by a stochastic genotoxic mechanism.
                                                                                       It acts by a non-stochastic genotoxic mechanism.
 (Regulation EC 1272/2008, Section 3.6 Carcinogenicity).3                              It acts by a non-genotoxic mechanism.
                                                                                       Its potential genotoxicity has been insufficiently investigated.
                                                                                       Therefore, it is unclear whether the compound is genotoxic.
                                                                              2        The compound is suspected to be carcinogenic to man.             2
                                                                              (3)      The available data are insufficient to evaluate the              not applicable
                                                                                       carcinogenic properties of the compound.
                                                                              (4)      The compound is probably not carcinogenic to man.                not applicable
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<pre> Annexes                                                                                                             Iron and steel founding emissions | page 49 of 87
 F         individual components that can                                         Table 1.1 (Geometric) mean air levels, data published after 1984
                                                                                   Substance name                 Mean     Lowest   Highest        Range Note
           be found in the emission during                                         Respirable dust
                                                                                                                   level
                                                                                                                  n.d.p.
                                                                                                                             level
                                                                                                                               580
                                                                                                                                       level
                                                                                                                                        580  20 – 31,000 Exposure level
                                                                                   (in air, µg/m3)                                                         depending on job title
           iron and steel founding                                                 Respirable quartz              n.d.p.        28        28
                                                                                                                                                           or content
                                                                                                                                                3 – 2,100 Exposure level
                                                                                   (in air, µg/m3)                                                         depending on job title
                                                                                                                                                           or content
                                                                                   Carbon monoxide                n.d.p.     n.d.p.   n.d.p.        n.d.p. No data
 Source IARC Monograph 100F (2012, pages 497 - 507),                               (in air, µg/m3)
 compilation of Table 1.1 and text in section 1.2                                  Binder components*:            n.d.p.        3.4     200   < 4 – 1,600 Exposure level
                                                                                   isocyanates                                                             depending on job title
                                                                                   (in air, µg/m3)                                                         or content
 “Substantial exposures to silica and carbon monoxide continue to occur in many    Polycyclic aromatic                                                     Exposure level
                                                                                   hydrocarbons                                                            depending on job title
 foundries. Occupational exposures to airborne polycyclic aromatic hydrocarbons
                                                                                   (in air, µg/m3):                                                        or content
 (PAHs) are also present, resulting mainly from the thermal decomposition of       -	Pyrene                      n.d.p.        0.0     0.22        n.d.p.
 carbonaceous ingredients commonly added to foundry sand. In addition, some steel  -	Benzo[a]pyrene              n.d.p.        0.0     0.04        n.d.p.
 foundry workers (e.g. fettlers) are exposed to airborne chromium and nickel       -	Sum of 15 PAHs              n.d.p.      0.58    11.17         n.d.p.
 compounds. The introduction of organic binder materials in the late 1950s has     Metals                                                                  Exposure level
 resulted in exposures of foundry workers to other chemicals, including phenol,    -	Thallium (in urine, µg/l)   n.d.p.      0.22      0.38  0.06 – 1.22  depending on job title;
                                                                                   -	Manganese                 2.5 ± 5     n.d.p.   n.d.p.        n.d.p. confirmed exposure
 formaldehyde, isocyanates and various amines. Earlier exposure studies have been      (in blood, µg/l)                                                    to lead and cadmium;
 reviewed previously (IARC, 1984). More recent studies are presented here and      -	Cadmium (in urine, µg/l)      9.52     n.d.p.   n.d.p. 3.19 – 22.07  data missing on job
 summarized in Table 1.1.”                                                         -	Cobalt (in urine, µg/l)       8.18     n.d.p.   n.d.p. 3.06 – 23.30  history
                                                                                   -	Nickel (in urine, µg/l)     33.10      n.d.p.   n.d.p.        13.90
                                                                                   -	Lead (in urine, µg/l)       53.50      n.d.p.   n.d.p.      – 78.90
                                                                                                                                                    28.90
                                                                                                                                                  – 85.60
                                                                                   Refractory ceramic fibres                                               Exposure level
                                                                                   - in fibres/mL air                 1     n.d.p.       23        n.d.p. depending on job title
                                                                                   - in fibres/cm3 of lavage  34 - 930      0.01      930 < 0.01 – 0.29
                                                                                       fluid
                                                                                  n.d.p., No data presented.
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<pre> Annexes                                                                                                                    Iron and steel founding emissions | page 50 of 87
 * Binder components. “Organic binder materials for cores and moulds include furan,       Source: IARC Monograph 34 (1984, pages 133 - 190), compilation of
 phenol-formaldehyde, urea-formaldehyde and urethane resins as well as oleo-resinous      Table 4 and text in section 3.1
 oils. These ingredients may volatilize into the workplace air during mixing, blowing,
 ramming, drying or baking operations. Curing reactions and thermal decomposition
 give rise to formation of additional compounds, which are released during pouring and    “A wide variety of occupational health hazards is present in iron and steel foundries:
 shakeout. When organic binders are subjected to high temperatures, pyrolysis may         airborne crystalline silica is virtually ubiquitous in foundries that use quartz and for
 produce gases and smoke aerosols. Only a few components of these emissions have          moulding and coremaking; metallic fumes are present during melting, pouring, welding
 been identified: aliphatic components include methane, ethane, ethylene, acetylene,      and flame-cutting processes; and metal dusts are associated with abrasive grinding
 and smaller amounts of high molecular-weight compounds; aromatic substances              operations. The cupola and casting operations may emit carbon monoxide into the
 include benzene, toluene, xylenes, naphthalenes and a variety of PAHs in lower           working environment. Phenol, formaldehyde, furfuryl alcohol, isocyanates and amines
 concentrations. Nitrogen compounds such as ammonia, cyanides and amines may be           are used as ingredients of organic binders in mould and core sands. Furthermore,
 formed from the nitrogen-containing urea, ammonium salts and                             several carbonaceous materials are in contact with molten metal during pouring and
 hexamethylenetetramine that are used as binder chemicals. Urethane resins may emit       thus various pyrolysis products, including polynuclear aromatic compounds, are
 free isocyanates under moulding and pouring conditions. No-bake catalysts, based on      formed.”
 arylsulphonic acids, may produce sulfur dioxide and hydrogen sulphide by thermal
                                                                                          “Main airborne contaminants to which workers may be exposed are given in Table 4.”
 processes. If phosphoric acid is used as a catalyst, phosphine can be formed in the
 strongly reducing atmosphere of the hot emissions. In air, phosphine rapidly oxidizes
 to phosphorus oxide. Furan binders contain free furfuryl alcohol, which can volatilize
 during mixing, moulding or core-making. Similarly, furan and phenolic resins may emit
 formaldehyde, phenol and other derivatives by volatilization or thermal decomposition.
 Core oils and alkyd-isocyanate resins are partly composed of natural drying oils, and
 heating of these materials gives rise to acrolein, various aldehydes, ketones, acids and
 esters as well as aliphatic hydrocarbons. When organic solvents are used in sand
 binders, the vapours may add to the exposure of workers (Toeniskoetter & Schafer,
 1977; IARC, 1984).”
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<pre> Annexes                                                                                                                                  Iron and steel founding emissions | page 51 of 87
 Table 4. A   irborne substances (and cases of substances) found in
             iron and steel foundriesa
  Material                             Principle uses or sources of emission                          Material                                Principle uses or sources of emission
  Common airborne contaminants                                                                        Hydrocarbons, aliphatic and             Solvents tor binders and paints, pattern resins and glues, core
                                                                                                      aromatic (e.g., benzene, toluene,       and mould dressings, metal primers, petroleum fuels, thermal
  (e.g., hexamethylenetetramine        Urethane binders, amine gassing of urethane resins, thermal
                                                                                                      xylene, naphthalene)                    decomposition of organic materials in foundry sand
  triethylamine;                       decomposition of urea, urethane or shell binders
  Dimethylethyl amine, aniline)                                                                       Hydrogen sulphide                       Water quenching of furnace slag, thermal decomposition of
                                                                                                                                              sulphur compounds in foundry sand
  Ammonia                              Thermal decomposition of hexamethylenetetramine in shell
                                       moulding, decomposition of urea or urethane binders            Iron and iron oxides                    Ferrous alloys, melting, pouring, cutting, grinding and welding
  Bentonite                            Foundry sand, refractory materials                             lsocyanates (e.g.,                      Urethane resins, thermal decomposition of urethane binders
                                                                                                      4,4’-methylenediphenyl diisocyanate)    in foundry sands
  Carbon                               Coal powder, graphite and soot in foundry sand, coke in
                                       cupola melting, core and mouId coatings, constituent of        Lead and lead oxides*                   Scrap melting, spray painting operations
                                       ferrous alloys, electrodes in arc melting and gouging
                                                                                                      Magnesium and magnesium oxide           lnoculation process in production of nodular iron
  Carbon dioxide                       Combustion of carbonaceous materials in foundry sand,
                                                                                                      Manganese and manganese oxides          Ferrous alloys, melting, pouring, cutting, grinding and welding
                                       cupola melting, fuel combustion in furnaces, ovens, heaters
                                                                                                                                              operations
                                       and engines, carbon dioxide gassing of silicate binders, inert
                                       gas welding                                                    Nickel and nickel oxides                Steel alloys, melting, pouring, cutting, grinding and welding
                                                                                                                                              operations
  Carbon monoxide                      Combustion of carbonaceous materials in foundry sand,
                                       cupola melting, fuel combustion in furnaces, ovens, heaters    Nitrogen oxides                         Thermal decomposition of urea or urethane binders in foundry
                                       and engines, flame cutting and welding                                                                 sand, flame cutting and welding, internal combustion engines
  Chromite                             Foundry sand, refractory materials                             Olivine                                 Foundry sand, refractory materials
  Chromium and chromium oxides         Steel alloys, melting, pouring, cutting, grinding and welding  Phenols (e.g., cresol, phenol, xylenol) Phenolic binders, thermal decomposition of organic materials
  (chromium VI, chromium III,          operations                                                                                             in foundry sand
  chromium metallic)
                                                                                                      Polynuclear aromatic hydrocarbons       Coal-tar pitch, thermal decomposition of carbonaceous
  Chlorinated hydrocarbons (e.g.,      Solvents                                                                                               materials in foundry sand, fuel combustion in furnaces, ovens,
  1,1,1-trichloroethane)                                                                                                                      heaters and engines
  Cristobalite                         Refractory materials, high-temperature transformation of       Silica, quartz                          Foundry sand, refractory materials, sand blasting
                                       silicon dioxide
                                                                                                      Sulphur dioxide                         Combustion of sulphurous fuels, sulphur-dioxide gassing and
  Fluorides                            Melting, slagging and welding                                                                          decomposition of furan resins
  Formaldehyde                         Urea, phenol and furan resins, thermal decomposition of        Tridymite                               Refractory materials, high-temperature, phase transformation
                                       organic materials in core baking and casting                                                           of quartz
  Furfuryl alcohol                     Furan resins                                                   Vanadium and vanadium oxides            Steel alloying
                                                                                                      (vanadium pentoxide)
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<pre> Annexes                                                                                                                                  Iron and steel founding emissions | page 52 of 87
 Material                                Principle uses or sources of emission                         Material                               Principle uses or sources of emission
 Zinc and zinc oxides                    Scrap melting                                                 Oxygen heterocyclics (e.g., furan,     Furan resins
                                                                                                       methylfuran)
 Zircon                                  Foundry sand, refractory materials
                                                                                                       Ozone                                  Inert gas welding
 Other airborne contaminants
                                                                                                       Phosphine                              Reaction of water with phosphides in ferroalloys,
 Acrolein                                Thermal decomposition of vegetable oils in care baking and
                                                                                                                                              decomposition of furan binder, furan resins catalysed with
                                         casting
                                                                                                                                              phosphoric acid
 Alcohols, aliphatic (e.g., isopropanol) Solvents tor binders and paints, carriers tor care and mould
                                                                                                       Phosphoric acid                        Catalyst for furan resins
                                         dressings, components of urethane resins
                                                                                                       Radon                                  Zircon sands
 Asbestos                                Thermal or electrical insulation in furnaces and ovens;
                                         coverings, troughs and clothing in pouring areas              Sulphonic acids (e.g., toluene/        Catalyst for furan resins
                                                                                                       sulphonic acid)
 Cadmium and cadmium oxide               Scrap melting
                                                                                                       Sulphur heterocyclics (e.g.,           Decomposition of furan resins
 Calcium carbide, calcium carbonate,     Melting, alloying and slagging
                                                                                                       thiophene)
 calcium silicide, calcium oxide
                                                                                                       Talc                                   Core and mould dressings
 Carbon disulphide                       Decomposition of furan resins with sulphonic acid catalysts
 Carbonyl disulphide                     Decomposition of furan resins with sulphonic acid catalysts  Note IARC: The list includes chemicals (or classes of chemicals) used in or formed in
 Copper and copper oxides                Scrap melting, are gouging with coated carbon electrodes
                                                                                                      iron and steel founding operations, and the processes during which they are used or
                                                                                                      formed or during which exposures are most likely to occur. It was compiled from
 Cyanides (e.g., hydrogen cyanide)       Thermal decomposition of urea or urethane binders, heat
                                         treatment of special castings                                information collected during the preparation of the monograph and cannot pretend to
                                                                                                      be exhaustive.
 Esters (e.g. glycerol diacetate, butyI  Ester-silicate process, foundry solvents
 acetate)
 Ethyl silicate                          Silicate binders
 Ferrochromium, ferromanganese,          Melting and alloying
 ferromolybdenum, ferrosilicon,
 ferrovanadium
 Methylethylketone peroxide              Sulphur-dioxide gassing process
 Nitrogen heterocyclics (e.g., pyridine) Coal-tar pitch, thermal decomposition of carbonaceous
                                         materials in foundry sand
 Nitrosamines (e.g., N-nitrosodimethyl- Reaction of nitrogen oxides with amines in foundry sand
 amine*, N-nitrosodiethylamine)
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<pre> Annexes                                                                                                    Iron and steel founding emissions | page 53 of 87
 G substances identified in the
                                                                        IARC classification                                Substance name
                                                                        Group 2B (the agent is possibly carcinogenic to    Cobalt
                                                                        humans)                                            Furan
            emissions of iron and steel
                                                                                                                           Furfuryl alcohol
                                                                                                                           Lead
                                                                                                                           Naphthalene
                                                                                                                           Nickel
            founding, which are classified                                                                                 Nitrosamines
                                                                                                                           Refractory ceramic fibres
                                                                                                                           Vanadium pentoxide
            for carcinogenicity                                         Group 3 (the agent is not classified as to its
                                                                        carcinogenicity to humans)
                                                                                                                           1,1,1-trichloroethane
                                                                                                                           4,4’-methylenediphenyl diisocyanate
                                                                                                                           Aniline
                                                                                                                           Chromium III compounds
                                                                                                                           Chromium metal
                                                                                                                           Ferrochromium
 Substances identified in the emissions of iron and steel founding,                                                        Fluorides
                                                                                                                           Lead
 which are classified for carcinogenicity by IARC (Source www.iarc.fr;
                                                                                                                           Phenol
 last visited, September 30, 2019)                                                                                         Pyrene (PAH)
                                                                                                                           Talc
                                                                                                                           Toluene
  IARC classification                             Substance name                                                           Xylene
  Group 1 (the agent is carcinogenic to humans)   Asbestos              Group 4 (the agent is probably not carcinogenic to -
                                                  Benzene               humans)
                                                  Benzo[a]pyrene (PAH
                                                  Cadmium
                                                  Cadmium oxide
                                                  Chromium VI compounds
                                                  Coal tar pitch
                                                  Cristabolite
                                                  Formaldehyde
                                                  Isopropanol
                                                  Nickel oxides
                                                  Respirable quartz
  Group 2A (the agent is probably carcinogenic to Lead oxides
  humans)                                         Nitrosamines
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<pre> Annexes                                                                                               Iron and steel founding emissions | page 54 of 87
 Substances identified in the emissions of iron and steel founding,          • Respirable crystalline silica
 which are classified for carcinogenicity in The Netherlands                 • Work that involves exposure to polycyclic aromatic hydrocarbons,
                                                                               which is present in soot and tar from coal
 Source: CMR-list of the Dutch Ministry of Social Affairs and Employment.    • Work that involves exposure to work activities that generate
 The list comprises substances classified in category 1A or 1B for             respirable crystalline silica
 carcinogens, according to the Dutch legislation (Staatscourant, website:
 https://zoek.officielebekendmakingen.nl; last visited, September 30, 2019).
 • Asbestos
 • Benzene
 • Benzo[a]pyrene
 • Cadmium
 • Cadmium oxide
 • Chromium VI compounds
 • Formaldehyde
 • Furan
 • Nickel oxide
 • Nitrosamines (e.g., N-nitrosodiethanolamine, N-nitrosodiethylamine,
    N-nitrosodiisopropylamine, N-nitrosodimethylamine, N-nitrosodi-n-
    butylamine, nitrosodipropylamine, N-nitrosomethylethylamine,
    N-nitrosomethylvinylamine, N-nitrosoethylureum,
    N-nitrosomethylureum, N-nitrosomorfoline, N-nitrosopiperidine,
    N-nitrosopyrrolidine)
 • Refractory ceramic fibres
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<pre> Annexes                                                                                                                            Iron and steel founding emissions | page 55 of 87
 H genotoxicity: mutagenicity in vitro
 Method and reference          Cell type and conditions          Source test substance and doses applied in          Results                                        Reliability (Annex B)
                                                                 test system
 Reverse mutation (Ames test)  Salmonella typhimurium TA98 and   Organic, cyclohexane soluble foundry air            TA98: positive (+S9)                           Only two strains tested; no
                               TA100, with (+) and without (-)   contaminants sampled in two iron foundries (A       TA100: positive (+S9)                          data on cytotoxicity; limited
 Skyttä et al. (1980)28        metabolic activation (S9)         and B). Samples obtained from breathing zone;       (samples contained 0.1-2.7 µg B(a)P per plate) statistical analyses; no further
                                                                 concentration of B(a)P ranged between 0.6-57.5                                                     details on concentrations
                                                                 µg/m3                                               Samples from plant A showed a dose-related     applied
                                                                                                                     correlation between the amount of B(a)P and
                                                                 Doses applied: single or two solutions of sample    mutagenicity, when compared to the             Reliability 2
                                                                 extracts (samples contained 0.1-2.7 µg B(a)P)       corresponding dose response correlations of
                                                                                                                     known B(a)P concentrations (correlation
                                                                                                                     coefficients):
                                                                                                                     -	TA98: 0.78
                                                                                                                     -	TA100: 0.87
                                                                                                                     -	B(a)P standard: 0.99
 Reverse mutation (Ames test)  Salmonella typhimurium TA98 and   Extracts of airborne particulates from breathing    TA98                                           Only two strains tested; no
                               TA100, with (+) and without (-)   zone from workers in two iron foundries (using      Positive in TA98 (+/- S)                       data on cytotoxicity; no data
 Bryant and McCalla (1982)29   metabolic activation (S9)         coal-tar pitch as an additive); no data reported on Positive dose-related response in TA98 with    on composition of extracts
                                                                 concentrations of particulate extracts used in test metabolic activation
                               spontaneous mutation rate in TA98 system, but figure 1 in paper shows                                                                Reliability 2
                               (15-20 revertants/plate) and in   concentrations of 0,100, 200, 500 and 750 µg        TA100
                               TA100 (150 rev/ plate)            particulate.                                        Negative
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<pre> Annexes                                                                                                                            Iron and steel founding emissions | page 56 of 87
 Method and reference         Cell type and conditions          Source test substance and doses applied in           Results                                          Reliability (Annex B)
                                                                test system
 Reverse mutation (Ames test) Salmonella typhimurium TA98 and   Iron foundry fumes sampled from 3 different          Positive in TA98 and TA100 (+/-S9) for all       Only two strains tested; no
                              TA100, with (+) and without (-)   binder systems (in casting area):                    binders:                                         results presented on positive
 Humfrey et al. (1996)8       metabolic activation (S9)         -	A: green sand binder                              -	A: TA98 (50/20), TA100 (80/50)                and negative controls
                                                                -	B: shell mould binder                             -	B: TA98 (30/60), TA100 (70/80)                (authors remarked that the
                                                                -	C: cold box amine gassed binder                   -	C: TA98 (690/130), TA100 (570/170)            positive control compounds
                                                                                                                                                                      “demonstrated the sensitivity
                                                                Doses applied: 0, 50, 150, 500, 1,500, and 5,000     Significant dose-related increase in number of   of the assay and the
                                                                µg extract/ml.                                       revertants (A, B and C): C was most potent       metabolic activity of the S-9
                                                                                                                     (description of authors, no data presented)      mix”; no data on statistical
                                                                Test include positive controls                                                                        analysis
                                                                                                                     Preliminary study did show cytotoxicity up to
                                                                                                                     5,000 µg/ml                                      Reliability 2
 Reverse mutation (Ames test) Salmonella typhimurium TA98, with Ferrous foundries; foundry-air particulate was       Foundry areas (foundry not specified):           Study design not appropriate
                              (+) and without (-) metabolic     collected and filtered, and all mould and core-      positive (+/- S9)
 Gibson et al. (1983)30       activation (S9)                   making materials were tested for mutagenicity;       + S9 gave higher mutation rates than -S9         Only one strains tested; lack
                                                                sampling at different sites in foundry (crane, core,                                                  of positive control, no
                                                                mould, finish, etc.)                                 Bulk of total mutagenicity associated with       statistical analyses; one dose
                                                                                                                     particulates <1.1 µm diameter                    applied only
                                                                Mean values of PAH in particulates (B[a]P µg/m3,
                                                                modified data from literature):                      Moulding materials: negative                     Reliability 3
                                                                Steel foundry: 0.43
                                                                Iron foundry: 0.94
 Reverse mutation (Ames test) Salmonella typhimurium TA98, with Steel foundry, Canada; collection of different size  Positive outcome (+S9) - The smaller the         Study design not appropriate
                              (+) and without (-) metabolic     classes of airborne particulate matter               particles the higher number of revertants per mg
 McCalla et al. (1983)31      activation (S9)                                                                        particulate                                      Only one strain tested; no
                                                                Samples collected 5 successive (size class, µm):     -	dose-related increase in revertants per plate data on spontaneous mutant
                                                                <1.1, 1.1-2.0, 2.0-3.3, 3.3-7.0, and >7.0; dose                                                       frequency; no data on positive
                                                                applied on plates: 0.5, 2.0 and 5 mg equivalents     No or lower positive scores without metabolic    controls; no data on
                                                                of particulates                                      activation.                                      cytotoxicity; no data on
                                                                                                                                                                      statistical analyses
                                                                Positive control: 2-acetylaminofluorene
                                                                                                                                                                      Reliability 3
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<pre> Annexes                                                                                                                                    Iron and steel founding emissions | page 57 of 87
 Method and reference                Cell type and conditions           Source test substance and doses applied in          Results                                      Reliability (Annex B)
                                                                        test system
 Reverse mutation (Ames test)        Salmonella typhimurium TA 98, with Extracts of emissions from binder systems used      +S9: positive for all binder systems         Study design not appropriate
                                     (+) and without (-) metabolic      in Steel Foundry; emission was generated when
 Kaiser-Farell et al. (1986)32       activation (S9)                    molten steel was poured into sand molds             -S9: positive for all binder systems.        Only one strain tested; data
                                                                        fabricated with different binder systems (1) shell                                               on controls not shown; no
                                                                        core, 2) conventional oil-clay-cereal, 3) new green Mutagenic activity:                          data on statistical analysis; no
                                                                        sand, 4) green sand with reclaimed silica sand, 5)  -	varied among binder types                 data on cytotoxicity
                                                                        green sand with reclaimed silica sand plus hot      -	higher in tests +S9 than in tests -S9
                                                                        topping compound, 6) sodium silicate, 7) furan                                                   Reliability 3
                                                                        no-bake, and 8) kold set). For each binder
                                                                        emission samples were taken.
                                                                        Positive controls: 2-acetylamino-fluorene,
                                                                        1-nitropyrene and 2-nitrofluorene
                                                                        Negative control: ambient background
 Reverse mutation (Ames test)        Salmonella typhimurium TA98 and    Steel foundry; air samples collected (breathing     Pouring-floor level:                         Secondary source available
                                     TA100 with and without metabolic   zone) on glass-fibre filters and extracted; no data TA98: positive (+/-S9)                       only
 Kaiser et al. (1981) (Source: IARC  activation (S9)                    on concentrations in tested samples.                TA100: negative (+/-S9)
 1984)5                                                                                                                                                                  Reliability 4
                                                                                                                            Floor level:
                                                                                                                            TA98: positive (+/-S9)
                                                                                                                            TA100: negative (+/-S9)
 Reverse mutations (Ames assay;      Urinary samples obtained from      Steel foundry                                       Result focuses on smoking habits; no results Only one strain tested; lack of
 Salmonella typhimurium TA98)        Canadian steel foundry workers                                                         shown for separate groups.                   detailed information on
                                     (N=125)                            No data on exposure or emission levels in                                                        results, such as number of
 Tomkins et al. (1990)33, Tomkins et                                    foundry                                             Reverse mutations (smoking status)           workers among groups, and
 al. (1986)34                        Groups:                                                                                -	never: 1.65-2.00 rev/ml                   number of smokers
                                     -	high-risk (crane operators)                                                         -	current: 3.81-4.09 rev/ml
                                     -	intermediate-risk (molders and                                                                                                  Reliability 4
                                         finishers)                                                                         No other data presented.
                                     - unexposed controls (office
                                         workers from elsewhere in the
                                         plant)
                                     Groups were matched for age,
                                     smoking history and years of
                                     exposure
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<pre> Annexes                                                                                                                          Iron and steel founding emissions | page 58 of 87
 I           genotoxicity in humans
 Gene mutation assays
  Method and reference         Cell type and conditions          Source test substance and doses applied in        Results                                        Remarks and reliability
                                                                 test system                                                                                      (Annex B)
  Somatic gene mutation (HPRT  Peripheral white blood cells from Finnish iron foundry                              HPRT mutations (mutation frequency/106 cells;  Small study
  locus)                       healthy iron male and female                                                        year 1, year 2 and year 1+2)):
                               foundry workers (N=64; 51 males,  8-Hour dust samples taken from stationary and     -	low:1.0±0.2, 1.1±0.5, 1.1±0.5               Data were adjusted for
  Perera et al. (1994)35       13 females)                       personal air monitoring; B(a)P was extracted from -	medium:1.1±0.2, 1.0±0.6, 1.1±0.5            smoking
                                                                 dust samples. Workers were placed in one of the -	high: 1.7±0.9, 0.9±0.0, 1.7±0.9
                               Average length of employment: 14  three exposure groups (in concentration of B(a)   No statistically significant differences found Variability in exposure levels
                               years (range 1 to 47 years)       P):                                                                                              within groups
                                                                 -	low: < 5 ng/m3, N=20
                               One or two samples were taken in  -	medium: 5-12 ng/m3, N=26                                                                      Reliability 2
                               November/ December 1990 (year 1)  -	high: >12 ng/m3, N=18
                               and/or in November/ December
                               1991 (year 2)
                               50% current smokers
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<pre> Annexes                                                                                                                                Iron and steel founding emissions | page 59 of 87
 Other genotoxicity tests
 Method and reference                Cell type and conditions           Source test substance and doses applied in       Results                                       Quality score (see Annex B)
                                                                        test system
 Micronuclei frequency               Peripheral lymphocytes obtained    Polish steel foundry                             Mean micronuclei frequency:                   Small study
                                     from steel foundry workers (N=91)                                                   -	Coke oven workers: 12.4±0.77, p=0.84
 Kubiak et al. (1999)9                                                  Ambient PAH levels at the work stand (mean µg    -	Rollers: 11.3 ± 0.59                       Information on smoking,
                                     Samples were taken in 1991, 1993   B(a)P/m3, 1991-1993-1996):                       Difference between groups not statistically   drinking, protective equipment
                                     and 1996                           -	coke oven unit workers, high exposure, N=55): significant                                   and current or prior
                                                                           9.69-3.05-13.72                                                                             occupational exposures
                                     Lymphocytes were cytokinesis-      -	Reference group (rollers with low exposure,   No relationship between micronuclei frequency
                                     blocked                               N=10): 0.006-nd*-nd*                          and duration of work.                         Reliability 2
                                                                        * not determined
                                                                        Mean 1-hydroxypyrene excretion in urine
                                                                        (µmoles/Mol creatinine):
                                                                        -	Coke oven workers: 10.78 ± 13.44 (p=0.0008)
                                                                        -	Rollers:0.76 ± 0.63
 Chromosome aberrations (CA);        Blood samples obtained from        Steel foundry                                    Result focuses on smoking habits; no results  Lack of detailed information
 Sister chromatid exchange (SCE);    Canadian steel foundry workers                                                      shown for separate groups.                    on results, such as number of
 micronuclei                         (N=125)                            No data on exposure or emission levels in                                                      workers in groups, and
                                                                        foundry                                          Smoking status                                number of smokers
 Tomkins et al. (1990),33 Tomkins et Groups:                                                                             % micronuclei
 al. (1986)34                        -	high-risk (crane operators)                                                      -	never: 0.57                                Reliability 4
                                     -	intermediate-risk (moulders and                                                  -	current: 0.57
                                        finishers)                                                                       No. of micronuclei/1,000 cells:
                                     - unexposed controls (office                                                       -	never: 5.98
                                        workers from elsewhere in the                                                    -	current: 6.03
                                        plant)                                                                           % cells with CA
                                                                                                                         -	never: 9.01
                                     Groups were matched for age,                                                        -	current: 11.31
                                     smoking history and years of                                                        Mean SCE per cell
                                     exposure                                                                            -	never: 14.80
                                                                                                                         -	current:16.22
                                                                                                                         No other data presented.
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<pre> Annexes                                                                                                                                 Iron and steel founding emissions | page 60 of 87
 Method and reference            Cell type and conditions              Source test substance and doses applied in        Results                                          Quality score (see Annex B)
                                                                       test system
 Chromosome aberrations (CA);    Peripheral lymphocytes obtained       No data on exposure levels; no data on            Data shown below concern adults only             Population-based study
 Sister chromatid exchange (SCE) from male and female inhabitants:     environmental emission levels from steel foundry;
                                 -	living nearby a steel foundry      no data on background emission levels             CA (% gaps, % other aberrations):                No data on exposure levels;
 Rudek (1990)36                     (N=9+21)*                                                                            -	Nearby: 1.14, 0.79                            no information on work
                                 -	living in central Kraków (N=8+12)*                                                   -	Kraków: 0.59, 0.65                            history; lack of data on
                                 -	living in a small village at 40 km                                                   -	Village: 0.28, 0.50                           workers in steel foundry
                                    distance from city and foundry                                                       (p<0.05)
                                    (N=8+12)*                                                                                                                             Data not relevant
                                                                                                                         SCE range (mean/cell):
                                 * Age groups                                                                            -	Nearby: 10.4±3.0
                                 7-15 yrs: children                                                                      -	Kraków: 7.9±3.0
                                 50-73 yrs: adults                                                                       -	Village: 6.0±2.0
                                 (children+ adults)                                                                      (p<0.01)
                                 Blood samples retrieved in the                                                          Limited data on smoking habits (past and present
                                 period 1986-1988; CA counted in                                                         smokers combined; SCE range (mean/cell) ):
                                 150-200 metaphases/ sample, SCE                                                         -	Nearby (N=5): 12.6±2.9
                                 counted in 50 metaphases/                                                               -	Kraków (N=5): 7.9±3.4
                                 sample                                                                                  -	Village (N=2): 6.1±2.9
                                                                                                                         No data on never smokers
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<pre> Annexes                                                                                                                              Iron and steel founding emissions | page 61 of 87
 DNA-adduct formation
 Method and reference           Cell type and conditions            Source test substance and doses applied in        Results                                            Quality score (see Annex B)
                                                                    test system
 Aromatic DNA adducts           Peripheral white blood cells from   Finnish iron foundry                              Mean no. of adducts/108 nucleotides (range)):      Small study
 (32P-postlabelling assay)      healthy iron foundry workers (N=24)                                                   -	low: 0.06 (0-0.6)
                                                                    Industrial hygiene measurements for PAH in        -	high/medium: 1.8 (0-10.0)                       Variability in exposure levels;
                                Unexposed controls: subjects from   1978-1980 (as B(a)P]). Workers divided into three -	controls: 0.2 (0-1.9)                           no data on statistical analysis
 Phillips et al. (1988)37       different parts of Finland (N=9)    exposure groups;
                                                                    -	low (<0.05 µg/m3), N=16                        Large amount of inter-individual variation as well Reliability 2
                                                                    -	medium (0.05-0.2 µg/m ), N=6
                                                                                              3
                                                                                                                      as in samples taken from the same individual,
                                                                    -	high (>0.2 µg/m3), N=2                         but at different times
                                                                                                                      No effect from smoking observed
 Aromatic DNA adducts           Peripheral white blood cells from   Finnish iron foundry                              Mean DNA adduct score:                             Small study
 (32P-postlabelling assay)      healthy iron male and female                                                          -	Low: 0.5-1.0
                                foundry workers (N=61)              Workers were divided into exposure groups: low    -	Medium: 1.4-2.0                                 No effects observed taking
                  38
 Reddy (1991)                                                       (N=24), medium (N=32) and high (N=5)              -	High: 2.0-2.8                                   into account for age or
                                Unexposed controls: (N=19)                                                            -	Control: 0.0-0.3                                smoking habits (57% were
                                                                    Industrial hygiene measurements for PAH in                                                           smokers)
                                DNA adduct expressed as scores      1978-1980 (as B(a)P);                             Highly significant correlation between estimated
                                (no. of adducts/108 nucleotides):   -	low (<0.05 µg/m3)                              exposure and adduct levels.                        No data on job history
                                0: <5                               -	medium (0.05-0.2 µg/m3)
                                1: 5-10                             -	high (>0.2 µg/m3)                                                                                 Reliability 2
                                2: 10-20
                                3: >20
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<pre> Annexes                                                                                                                          Iron and steel founding emissions | page 62 of 87
 Method and reference          Cell type and conditions           Source test substance and doses applied in      Results                                           Quality score (see Annex B)
                                                                  test system
 Aromatic DNA adducts          Peripheral white blood cells from  Finnish iron foundry                            Mean DNA adducts (adducts/108 nucleotides,        Small study
 (32P-postlabelling assay)     healthy iron male and female                                                       adjusted for smoking habits):
                               foundry workers (N=48; 37 males,   Personal exposure to PAH (determination of B(a) -	Low: 5.1±4.1                                   Large inter-individual
 Santella et al. (1993)39      11 females)                        P) ranged between 2 and 60 ng/m3):              -	Medium: 6.1±4.3                                variability; study did not
                                                                  -	Low: < 5 ng/m3                               -	High: 9.6±8.1                                  include reference group
                               Employment period ranges from 2    -	Medium: 5-12 ng/m3                           Dose-related increase with exposure (r=0.28,      without exposure, lowest
                               to 46 years (average 13 years)     -	High: >12 ng/m3                              p=0.08); exposure groups did not differ           exposure group served as
                                                                                                                  significantly from each other                     reference
                                                                  Mean 1-hydroxypyrene levels (µmol/mol
                                                                  creatinine) in group:                           No Influence of cigarette smoking on formation of Reliability 2
                                                                  -	Low: 2.7±2.2                                 DNA adducts (54% of workers were smokers)
                                                                  -	Medium: 1.8±1.2
                                                                  -	High: 3.6±2.5
 Aromatic DNA adducts          Peripheral white blood cells from  Finnish iron foundry                            Aromatic DNA adducts (mean no. of adducts/108 Small study
 (32P-postlabelling assay)     healthy iron male and female                                                       nucleotides; year 1, 2, 1+2)
 PAH-DNA adducts (competitive  foundry workers (N=64; 51 males,   Workers were divided into exposure groups (in   -	low: 2.2±0.8, 1.3±0.6, 1.9±0.9                 Adjustments made for
 ELISA)                        13 females)                        B(a)P):                                         -	medium: 2.1±1.4, 1.5±1.1, 2.0±1.4              smoking
                                                                  -	low: < 5 ng/m3, N=20                         -	high: 2.5±1.2, 2.3±2.0, 2.5±1.2
 Somatic gene mutation (HPRT   Average length of employment: 14   -	medium: 5-12 ng/m3, N=26                                                                       Variability in exposure levels
 locus)                        years (range 1 to 47 years)        -	high: >12 ng/m3, N=18                        PAH-DNA adducts (mean no. of adducts/108          within groups; study did not
                                                                                                                  nucleotides; year 1,year 2 and year 1+2)):        include reference group
 Perera et al. (1994)35        One or two samples were taken in                                                   -	low: 5.2±4.1, 1.5±1.4, 4.4±3.9                 without exposure, lowest
                               1990 (year 1) and/or in 1991 (year                                                 -	medium: 6.1±4.3, 2.9±3.1, 5.2±4.2              exposure group served as
                               2)                                                                                 -	high: 9.6±8.1*, 3.9±4.1, 9.6±8.1               reference
                                                                                                                  * p<0.05 (low versus high exposure)
                               50% current smokers                                                                                                                  Reliability 2
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<pre> Annexes                                                                                                                                      Iron and steel founding emissions | page 63 of 87
 J           epidemiology: meta-analyses
 Note: heterogeneity p<0.10 is indicative for substantial heterogeneity
 (variation between studies)
  Selected studies and study population       Study selection criteria                    Results                                                                     Remarks and reliability ( Annex C)
  Cohort studies on workers employed in       Search period: up to February 2016          Outcome: no associations found                                              Appropriate design and reporting
  iron and steel foundries with data on
  lymphatic and haematopoietic neoplasms      Inclusion criteria: workers exposed to PAH; Meta-relative risks (95% confidence interval, number of cases,              No quality assessment of individual
  (N=12)*                                     incidence or mortality risk from (non-)     I-squared (%), p for heterogeneity:                                         studies performed; smoking habits
                                              Hodgkin lymphomas, multiple myeloma or                                                                                  not taken into account
  Alicandro et al. (2016)12                   leukemia, related to PAH exposure;          Hodgkin lymphoma
                                              publications in English, French or Italian; 1.38 (0.95-2.01), 26 cases, 0%, p=0.53                                      Reliability 2
  * Decoufle et al. 1979; Anjelkovisch et al. cause specified according to international
  1990; Moulin et al. 1990; Sherson et al.    classification of diseases                  Non-Hodgkin lymphoma
  1991; Rotimi et al. 1993; Hansen et al.                                                 0.94 (0.73-1.22), 57 cases, 0%, p=0.87
  1997; Firth et al. 1999; Park et al. 2005;  Quality assessment individual studies: not
  Hoshuyama et al. 2006; Westberg et al.      reported                                    Multiple myeloma
  2013; Yoon and Ahn 2014. Details of the                                                 1.00 (0.67-1.51), 23 cases, 0%, p=0.26
  individual studies are shown in Annex K     Meta-analyses: incidence ratios (SIR),
  (indicated as B)                            Standardized mortality ratios (SMR) and     Leukaemia
                                              relative risks (RR) with corresponding 95%  1.13 (0.93-1.39), 103 cases, 4%, p=0.41
                                              confidence intervals; analyses on
                                              heterogeneity, random effect models;        No significant between-study heterogeneity was observed; no indications for
                                              sensitivity analyses performed              publication bias
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<pre> Annexes                                                                                                                                           Iron and steel founding emissions | page 64 of 87
 Selected studies and study population         Study selection criteria                       Results                                                                          Remarks and reliability ( Annex C)
 Cohort studies on workers employed in         Search period: 1958 – 2014                     Outcome: positive association for certain cancer types                           Appropriate design and reporting
 industries with potential PAH exposure
 (N=13, iron and steel foundries)*             Inclusion criteria: cancer/tumours on          Standard mortality ratios (SMR) and pooled relative risk (RR) (95% confidence    No quality assessment of individual
                                               respiratory and urinary tracts; PAH            interval), observed/expected, p value for heterogeneity:                         studies performed; smoking habits
 Rota et al. (2014)10,                         exposure; retrospective, longitudinal and                                                                                       not taken into account
 Update from Bosetti et al. (2006)             prospective cohorts; one publication per       Respiratory tract
                                               cohort (most informative); cancer cases        -	all: SMR 1.05, pooled RR 1.31 (1.08-1.59), 2,932//2,784, p<0.0001             Authors report that workers may be
 * Koskela et al. 1976; Gibson et al. 1977;    and deaths                                     -	lung cancer: SMR 1.05, pooled RR 1.31 (1.07-1.61), 2,903/2,762, p<0.0001      exposed in the past to various
 Breslin 1979; Andjelkovich et al. 1990;                                                      -	larynx: SMR 1.43, pooled RR 1.48 (1.14-1.91), 59/41, p=0.537                  potential carcinogenic substances
 Hansen 1991; Sherson et al. 1991; Rotimi      Quality assessment individual studies: not                                                                                      other than PAH
 et al. 1993; Sorahan et al. 1994; Moulin et   included                                       Bladder cancer
 al. 2000; Adzersen et al. 2003; Park et al.                                                  SMR 1.18, pooled RR 1.38 (1.00-1.91), 151/127, p=0.001                           Reliability 2
 2005; Hoshuyama et al. 2006; Westberg et      Meta-analyses: standard mortality ratios,
 al. 2013. Details of the individual studies   pooled relative risks; random-effects          Cancer in the kidneys
 are shown in Annex K (indicated as C)         models to take into account heterogeneity      SMR 0.98, pooled RR 1.03 (0.78-1.35), 68/69, p=0.304
                                               Heterogeneity: p<0.10 is indicative for
                                               substantial heterogeneity (variation
                                               between studies)
 Cohort studies on workers in the iron and     Search period: Up to December 2005             Outcome: positive association for cancer in the lungs, respiratory tract and the Appropriate design and reporting
 steel foundry with potential PAH exposure                                                    bladder; no association for kidney cancer
 (N=10)*                                       Inclusion criteria: workers in industries with                                                                                  No quality assessment of individual
                                               high PAH exposure; cohort design;              Order: standardized mortality ratio (SMR), observed/expected no. of cases,       studies performed; smoking habits
                     11
 Bosetti et al. 2006                           mortality or incidence data on cancer risk     pooled RR (95% confidence intervals), p=value for heterogeneity                  not taken into account
                                               (the lungs, the respiratory tract, the
                                               bladder, the urinary tract)                    Lung cancer (9 cohorts)                                                          Reliability 2
                                                                                              SMR, 1.39, 975/703.7, 1.40 (1.32-1.49), p=0.007
 *Koskela et al. (1976), Gibson et al.         Quality assessment individual studies: not Respiratory tract cancers (10 cohorts)
 (1977), Breslin et al. (1979), Decouflé       performed or reported                          SMR, 1.38, 1,004/726, 1.40 (1.31-1.49), p=0.012
 (1979), Andjelkovich et al. (1990), Hansen                                                   Bladder cancer (7 cohorts)
 (1991), Sherson et al. (1991), Rotimi et al. Meta-analysis: pooled relative risk (RR;        SMR, 1.19, 99/83, 1.29 (1.06-1.57), p<0.001
 (1993), Sorahan et al. (1994), Moulin et al. calculated as a weighted average of the         Kidney cancer (4 cohorts)
 (1993). Details of the individual studies are SMRs, using the inverse of the variance        SMR, 1.29, 40/31, 1.30 (0.095-1.77), p=0.91
 shown in Annex K (indicated as D)             as weight), fixed-effects model, chi-square
                                               test for heterogeneity
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<pre> Annexes                                                                                                                                       Iron and steel founding emissions | page 65 of 87
 Selected studies and study population     Study selection criteria                    Results                                                                            Remarks and reliability ( Annex C)
 Cohort studies on workers employed in     Search period: 1977-2017                    Outcome: Focus on PAH exposure, not on iron and steel founding per se,             Appropriate design
 industries with potential PAH exposure                                                therefore only a limited number of studies included. Two of the three studies also
 (N=3, iron and steel foundries, total of  Inclusion criteria: lung cancer/tumours;    included in Rota, for the 3rd study the reference is questionable (conference      Presentation of data is limited; no
 5,658 subjects)*                          sufficient data on level of PAH exposure;   abstract only). Therefore this publication is not relevant.                        data on heterogeneity for subgroup
                                           retrospective, longitudinal and prospective                                                                                    ‘iron and steel foundries’; no quality
 Singh et al. 201813                       cohorts; one publication per cohort (most   Pooled relative risk (95% confidence interval)                                     assessment of individual studies
                                           informative); cancer cases and deaths                                                                                          performed; smoking habits not taken
 * Gibson et al. 1977; Moulin et al. 2000; (mortality and incidences); publication in  Lung cancer                                                                        into account, because of limited
 Koskela et al. 1997. Details of the       English only                                1.52 (1.05-2.21), 135 cases (incidence and mortality combined)                     number of studies with data on
 individual studies are shown in Annex K                                                                                                                                  smoking
 (indicated as A)                          Quality assessment individual studies: not  Authors reported on wide variation in smoking habits and exposure to PAH, but
                                           included                                    data on PAH exposure levels not reported                                           Reliability 2
                                           Meta-analyses: standard mortality ratios,
                                           pooled relative risks; random-effects
                                           models to take into account heterogeneity;
                                           fixed effect models
                                           Subgroup analyses: job title
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<pre> Annexes                                                                                                      Iron and steel founding emissions | page 66 of 87
 K           epidemiology: cohorts studies
 A, B, C, D
            Data of the study used in meta-analysis by Singh et al. 2018 (A), Alicandro et al. 2016 (B), Rota et al. 2014 (C), and/or Bosetti et al. 2006 (D).
 Prospective cohort studies
  Study design and        Data on exposure and health Results Remarks and reliability
  population              assessment                          (annex C)
  No studies.
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<pre> Annexes                                                                                                                                    Iron and steel founding emissions | page 67 of 87
 Retrospective cohort studies (data on smoking habits)
 Study design and population              Data on exposure and health                Results                                                                           Remarks and reliability
                                          assessment                                                                                                                   (annex J)
 Iron and steel foundries (N=2); South    Exposure: data on work area/job classes;   Outcome: positive association with “all types of cancer”; no association with     Appropriate study design, large
 Korea; male workers (N=44,974)           personal breathing zone air sampling       individual types of cancer                                                        study
 employed between 1968-2001 and who       (obtained from one plant during 1994-
 were alive in 1992; follow-up 1992-2001  2000, probably representing worst case     During follow-up: 806 death cases (=2% of population at risk)                     No analyses performed on exposure
 (10 years); reference group, general     scenarios), substances identified were for                                                                                   levels of substances
 Korean male population                   instance benzene, chromium and other       Standardized rate ratio (95% confidence interval, number of deaths)
                                          metals, PAH, and carbon monoxide; data     -	stainless steel production areas:                                              Reliability 2
 B,C
    Park et al. (2005)40                  on duration of employment                  -	all cancer: 3.26 (1.37-6.49), N=7
 Note by the DECOS: most likely partly    Data: deaths identified by the Korean      No associations found regarding:
 overlap of the study population with the National Statistical Office; diseases      -	type of cancer
 populations in the studies by Yoon and   classified according to International      -	duration of employment
 Ahn (2014)41 and Ahn et al. (2010)42     Classification of Diseases; analyses
                                          included lag-time                          Authors reported large healthy worker effect for “all death causes”, and “cancer”
                                          Smoking habits obtained from part of       Smoking habits: during follow-up percentage of smokers decreased in both
                                          workers                                    foundries (Plant 1 from 59.9% to 14.4%; Plant 2 from 55.4% to 33.3%).
                                                                                     Authors note “The current smoking rate was similar across categories of last job.
                                                                                     The overall smoking rate of study subjects in 1994 was about 15% lower than that
                                                                                     of Korean male population in that year in the same age range”.
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<pre> Annexes                                                                                                                                  Iron and steel founding emissions | page 68 of 87
 Study design and population            Data on exposure and health                Results                                                                      Remarks and reliability
                                        assessment                                                                                                              (annex J)
 Iron foundries (N=10); Sweden; male    Exposure: respirable dust and quartz       Outcome: positive association with lung cancer                               Appropriate study design
 workers employed for at least 1 year   measurements (340 personal samples
 between 1913-2005 (N=3,045); morbidity taken between 2005-2006) plus historical   Standardized incidence ratios (95% confidence interval, expected/ observed)  Authors performed internal
 data obtained between 1958-2004;       measurement data from surveys from the     (data without taking into account smoking habits)                            comparison in their dose-response
 reference group, general population of 1960s                                                                                                                   analyses to adjust for differences in
 Sweden                                                                            Only data shown with statistically significant increased SIR                 smoking habits or other confounders
                                        Morbidity: data retrieved from company                                                                                  between foundry workers and the
 B,C
    Westberg et al. (2013)17            personnel records, and Swedish cancer      All workers                                                                  general population: the increased
                                        Registry; diseases classified according to -	all cancer types: 1.00 (0.90-1.11), 347.2/347                             lung cancer risk disappeared when
                                        International Classification of Diseases   -	primary lung cancer: 1.61 (1.20-2.12), 32.24/52                           the exposure groups were
                                                                                                                                                                compared.
                                        Smoking habits were obtained by            Duration of exposure
                                        questionnaire among 500 participants;      No association between duration of exposure and cancer development           Reliability 2
                                        percentage of ex-smokers and smokers
                                        were 68%, 65% and 84% in the low-          Latency time and duration of employment (lung cancer)
                                        medium and high-exposed groups             -	Latency 0-19 yrs: no association
                                        (exposure to respirable quartz), data on   - Latency ≥ 20 yrs
                                        individual smoking habits were not         -	duration 10-19 yrs: 2.35 (1.12-4.31), 4.27/10
                                        available.                                 - duration ≥ 20 yrs: 1.72 (1.08-2.61), 12.76/22
                                                                                   Latency time and cumulative quartz exposure (lung cancer)
                                                                                   -	Latency 0-19 yrs: no association
                                                                                   - Latency ≥ 20 yrs
                                                                                   -	low exposure: 2.05 (1.32-3.02), 12.22/25
                                                                                   -	medium exposure: 1.72 (1.00-1.75), 9.89/17
                                                                                   -	high exposure: 1.26 (0.26-3.69), 2.38/3
                                                                                   No dose-related trend observed
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<pre> Annexes                                                                                                                                          Iron and steel founding emissions | page 69 of 87
 Study design and population                  Data on exposure and health                  Results                                                                         Remarks and reliability
                                              assessment                                                                                                                   (annex J)
 Nested case-control study from               Complete work histories of cases and         Outcome: positive association with lung cancer in workers handling material; no Appropriate study design
 retrospective cohort described by            controls obtained from plant personnel       association among workers with other job activities
 B,C,D
      Rotimi et al. (1993); one iron foundry; files; information on other lung cancer risk                                                                                 Lack of data on exposure levels; no
 the USA; total number of lung cancer         factors, including cigarette smoking, was    Odds ratios (95% confidence intervals, cases/controls), lung cancer mortality   data on other types of cancer;
 cases is 231; 408 controls                   collected by interview.                                                                                                      adjustments made for smoking
                                                                                           Working area/job activities in iron foundry only (adjusted for smoking)         habits
 Note (1): cases and control represent total  Mortality: from death certificate; cases     -	Quality control: 6.3 (0.71-56), 6/1
 of one iron foundry and two engine plants    include 9 cases with lung cancer as          -	Material handling: 5.1 (1.5-17), 13/6                                        Reliability 2
 (data on iron foundry alone not reported)    secondary cause of death                     -	Maintenance: 0.87 (0.54-1.4), 31/62
 Note (2): cohort by B,C,DRotimi et al.                                                    -	Core room: 1.0 (0.57-56), 21/41
 (2013)43 not described in the present                                                     -	Melting: 0.10 (0.01-1.5), 1/6
 report, because no distinction is made                                                    -	Molding: 1.0 (0.48-2.1), 14/24
 between different types of industries                                                     - Cleaning/finishing: 0.92 (0.44-1.9), 15/28
 Austin et al., (1997)44                                                                   Duration of employment at iron foundry
                                                                                           -	non: 1.0 (-), 82/139
                                                                                           -	<10 yrs: 0.79 (0.49-1.3), 53/104
                                                                                           -	10-19 yrs: 1.1 (0.66-1.8), 45/67
                                                                                           - ≥20 yrs: 0.90 (0.55-1.5), 51/98
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<pre> Annexes                                                                                                                                      Iron and steel founding emissions | page 70 of 87
 Study design and population                 Data on exposure and health                  Results                                                                         Remarks and reliability
                                             assessment                                                                                                                   (annex J)
 Historical prospective cohort, including a  Exposure: assessed by job history            Outcome: no associations found                                                  Appropriate study design
 nested case-control study; one stainless    (specific job-exposure matrix); mean
 steel and metallic alloys plant; France;    duration of employment, 16.7 years;          Lost in follow-up, 1%                                                           Lack of objective exposure levels;
 male and female workers ever employed       exposure levels of certain substances                                                                                        data on smoking habits available
 for at least one year between 1968 and      based on knowledge of exposure levels        Historical cohort
 1991 (N=4,288 males, 609 females);          that might have occurred (for the nested     Standardized mortality ratios (95% confidence interval), expected/ observed     Moulin et al. 1993: “A survey of
 follow-up mortality 1968-1992 (mean         case-control study)                          (adjusted for sex and age)                                                      smoking habits
 length 18 years); reference group, general                                                                                                                               performed among
 French male population                      Mortality: death certificates (INSERM),      Malignant neoplasms                                                             those in employment 1986
                                             diseases classified according to             -	men: 0.98 (0.85-1.12), 210.3/206                                             (24% of the cohort) showed a
 A,C
    Moulin et al. 200019 (earlier results on International Classification of Diseases     -	both sexes: 0.82 (0.85-1.11), 222/216                                        slightly higher percentage of
 cohort published: B,DMoulin et al. 1993)45                                               Lung cancer: not increased                                                      smokers among the SS plant
                                             Analyses included confounding factors,       Bladder cancer: not increased                                                   workers, than in the national
                                             such as smoking habits                                                                                                       average. This could not explain the
                                                                                          Nested case-control study (odds ratios, 54 cases/162 controls)                  high lung cancer rate in
                                                                                          PAH and silica exposure: increased trends observed by increasing duration of    the foundry workers.”
                                                                                          exposure (PAH, OR 1.46, p=0.01; silica, OR 1.55, p<0.01) and estimated
                                                                                          increased exposure levels (PAH, OR 1.42, p=0.06; silica, OR 1.32, p=0.04)       Reliability 2
                                                                                          No significant differences:
                                                                                          -	smokers versus non-smokers
                                                                                          -	among job categories
                                                                                          -	by substance (metals, asbestos)
 Steel foundry, Dominion Foundries and       Exposure: foundry (N=439, working in         Outcome: positive association with lung cancer                                  Appropriate study design
 Steel Ltd, Canada; workers (in the past     foundry for at least 5 years) and
 and present) alive in 1967 and over 45      non-foundry group (N=1,103, at least 5       Standardized mortality ratios (SMR, 95% confidence interval, expected/observed) A smoking survey in 1973 showed
 years of age, N=1,542; reference group,     year working in plant, but less than 5 year                                                                                  no difference in
 urban population in Toronto                 in foundry); job categories; in 1967         Lung cancer                                                                     smoking habits
                                             exposure levels were measured (personal      -	Foundry: 2.55 (1.55-3.82), 8.4/21, p<0.005                                   between foundry
 A,C,D
      Gibson et al. 197746                   sampling, particulates and metals)           -	Non-foundry: 0.66 (0.33-1.19), 16.58/11                                      and non-foundry
                                                                                          -	exposure > 20 yrs                                                            workers
                                             Mortality: death certificates from attending -	foundry (N=128): 2.59, 1.25/11, p=0.025
                                             physician and insurance carrier; cause       -	non-foundry (N=640): 0.69, 11.59/8                                           Limited data on confidence intervals
                                             specified according to international
                                             classification of diseases                   All cancer                                                                      Reliability 2
                                                                                          Foundry: 1.38 (no data), 26.75/37, p<0.01
                                                                                          Non-foundry: 0.92 (no data), 53.27/49
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<pre> Annexes                                                                                                                                   Iron and steel founding emissions | page 71 of 87
 Study design and population               Data on exposure and health                Results                                                                    Remarks and reliability
                                           assessment                                                                                                            (annex J)
 Cohort study plus nested case-control     Exposure: air samples (including breathing Outcome: positive association with lung cancer and leukaemia               Small study
 study; gray iron foundry; the USA; male   zone) taken 17 times between 1947 and
 and female workers, employed for at least 1976; exposure levels determined of dust,  Standardized proportional mortality rates (95% confidence interval):       Data on standardized proportional
 10 years and who died between 1970-       carbon monoxide and other contaminants     All cancers:                                                               mortality rates is notoriously prone
 1981 (n=278); reference group, general    (PAH); exposure classification made by     -	white workers (N=221): 1.18 (0.95-1.47), 61 cases                       to bias; no data on exposure levels
 population, US death registry             type of work                               -	nonwhite workers (N=56): 1.17 (0.71-1.93), 12 cases                     presented
                                                                                      Lung cancer:
 Silverstein et al. (1986)47               Mortality: based on records using various  -	white workers: 1.48 (1.04-2.10), 28 cases                               Reliability 4
                                           sources, such as local union death benefit -	nonwhite workers: 0.85 (0.17-2.49), 3 cases
                                           fund and Social Security Administration;   Leukaemia:
                                           diseases classified according to           -	white workers: 2.84 (1.23-6.55), 5 cases
                                           International Classification of Diseases;  -	nonwhite workers: 0 cases
                                           smoking habits were recorded (71% of
                                           workers were classified as ever smokers)   Ever smokers had higher risks than non-smokers (white workers):
                                                                                      All cancers:
                                           Some data adjusted for age, formerly       -	never (N=45): 0.70 (0.38-1.27), 8 cases
                                           employed in coal mines or other foundries, -	ever (N=167): 1.30 (1.30-1.66), 51 cases, p<0.05
                                           and smoking habits                         Lung cancer:
                                                                                      -	never: 0.96 (0.24-2.44), 4 cases
                                                                                      -	ever: 1.59 (1.08-2.33), 23 cases, p<0.05
                                                                                      Nested-case control study:
                                                                                      No associations observed between type of work and lung cancer development.
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<pre> Annexes                                                                                                                                         Iron and steel founding emissions | page 72 of 87
 Retrospective cohort studies (no data on smoking habits)
 Study design and population                  Data on exposure and health                  Results                                                                           Remarks and reliability
                                              assessment                                                                                                                     (annex J)
 Iron and steel foundries (N=208); South      Exposure: based on job title, jobs           Outcome: positive association among production workers for stomach and lung       Appropriate study design
 Korea; N=14,611 male workers (between        classified in categories, year first         cancer; no associations found for colon, liver, pancreas and urinary bladder
 1992-2000; N=11,793 production workers;      employed, age first employed                 cancer                                                                            No data on smoking habits or other
 N=2.818 non-production workers);                                                                                                                                            lifestyle factors that may have
 follow-up first day of employment or         Mortality: data retrieved from Korea         Standardized mortality ratio (95% confidence interval), no. observed cases        influenced the outcome; no data on
 January 1992 up to December 2008;            National Statistical Office; causes of death (reference, Korean men):                                                          exposure levels
 reference group, Korean male population,     classified according to International        Stomach: 1.08 (0.81-1.41), 53
 and non-production workers in foundries      Classification of Diseases                   Lung: 1.06 (0.80-1.38), 56                                                        Reliability 2
 (not exposed)
                                                                                           Relative risk (compared to non-production workers) (95% confidence interval), no.
 B
  Yoon and Ahn 201441                                                                      observed cases:
                                                                                           All types: 1.90 (1.36-2.64), 274
 Note by the DECOS: most likely partly                                                     Stomach: 3.96 (1.41-11.06), 53
 overlap of the study population with the                                                  Lung: 2.08 (1.01-4.30), 56
 populations in the studies by Park et al.
 (2005)40 and Ahn et al. (2010)42
 Nested-case control study, Swedish           Exposure: see Westberg et al. (2013),        Outcome: no associations found regarding exposure to quartz                       Appropriate study design, small
 cohort; iron foundries (N=10); 52 cases of   focus on exposure to quartz; data                                                                                              study
 lung cancer; for each case 5 controls were   presented on job titles                      No association found between iron foundry work (expressed as quartz exposure)
 used                                                                                      and lung cancer risk                                                              No data on smoking habits, or
                                              Data: data retrieved from company                                                                                              socioeconomic status
 Andersson et al. (2012)48                    personnel records, and Swedish cancer        Highest odds ratio for lung cancer: 1.17 (95% confidence interval 0.53-2.55) for
                                              Registry; diseases classified according to   medium exposure group (1-1.9 mg quartz dust/m3)                                   Reliability 2
 (for cohort details see also Westberg et al. International Classification of Diseases
 2013)17
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<pre> Annexes                                                                                                                                     Iron and steel founding emissions | page 73 of 87
 Study design and population               Data on exposure and health                Results                                                                         Remarks and reliability
                                           assessment                                                                                                                 (annex J)
 Small-sized iron foundries; South Korea   Exposure: based on job title (production   Outcome: positive association with lung cancer and lympho-haematopoietic        Appropriate study design
 (N=208); N=17,098 male and female         (N=13,100) and office work (N=3,998)),     cancer
 workers, working any time between         and job area                                                                                                               No data on smoking habits
 1992-2000; reference group, Korean                                                   Standardized Incidence Rate Ratio (SIR, 95% confidence interval, number of
 general population; follow-up, cancer     Cancer incidence: data retrieved from      cases)                                                                          Reliability 2
 diagnosis between 1992-2005               Korea Central Cancer Registry; statistical
                                           analyses included adjustments for          Only data shown with statistically significant increased SIR
                   42
 Ahn et al. (2010)                         confounding factors (sex and age)
                                                                                      Types of cancer among production workers:
 Note by the DECOS: most likely partly                                                -	all cancers: 1.14 (1.03-1.26), 409
 overlap of the study population with the                                             -	lung cancer: 1.45(1.11-1.87), 61
 populations in the studies by Park et al.                                            -	lympho-haematopoietic cancer: 1.58 (1.00-2.37), 23
 (2005)40 and Yoon and Ahn et al. (2014)42
                                                                                      Job duration:
                                                                                      Less than 10 years:
                                                                                      -	all cancers: 1.22 (1.07-1.37), 261
                                                                                      -	stomach cancer: 1.35 (1.05-1.71), 68
                                                                                      -	lung cancer: 1.66 (1.20-2.24), 43
                                                                                      -	lympho-haematopoietic cancer: 1.81 (1.01-2.99), 15
                                                                                      More than 10 years: no exposure-related increase in any type of cancer observed
                                                                                      Most cases of lung and stomach cancer were found in production workers during
                                                                                      moulding and core making, and fettling
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<pre> Annexes                                                                                                                                          Iron and steel founding emissions | page 74 of 87
 Study design and population                Data on exposure and health                  Results                                                                             Remarks and reliability
                                            assessment                                                                                                                       (annex J)
 Iron steel plant; Anshan, China; male iron Exposure: assessment by job exposure         Outcome: positive association with lung cancer when combined PAH-exposure           Appropriate study design
 and steel workers, at least employed for   matrix, job title; exposure to 15 agents     with one or two other dust types
 six months and alive in 1980 (N=50,134);   assessed (yes/no exposure), exposure                                                                                             No data on smoking habits or other
 follow-up 14 yrs (1980-1993); internal     was linked by one job only                   Standardized mortality ratios (SMR) (95% confidence interval, no. of observed       lifestyle factors; limited data on
 reference group, non-exposed blue-collar                                                cases):                                                                             actual exposure levels; SMR
 workers (N=39,048); reference group,       Data: data retrieved from company            Lung cancer:                                                                        analyses showed healthy worker
 male population in Angang and residential  personnel records and company death          -	exposed workers: 0.96 (0.88-1.02), 750 cases                                     effect
 area of Anshan                             registry, municipal death registry; diseases -	internal reference: 0.88 (0.80-0.96), 507 cases
                                            classified according to International        Liver cancer:                                                                       Reliability 2
 B,C                         49
    Hoshuyama et al. (2006)                 Classification of Diseases                   -	exposed workers: 0.85 (0.76-0.94), 376 cases
                                                                                         -	internal reference: 0.81 (0.72-0.92), 265 cases
                                                                                         Stomach cancer:
                                                                                         -	exposed workers: 0.86 (0.77-0.96), 321 cases
                                                                                         -	internal reference: 0.81 (0.72-0.92), 225 cases
                                                                                         Specified by exposure agents (standardized rate ratios (SRR)):
                                                                                         -	silica, coal, grinding, wood and carbon monoxide: no association with cancer
                                                                                         -	iron, welding, cement, asbestos, heat, PAH, oil mist, acid mist, benzene:
                                                                                            positive association for different types of cancer, such as cancer in the lungs,
                                                                                            stomach, and liver (SRR >1.00 with 95% confidence intervals > 1.00)
                                                                                         Combined exposure to PAH and one or two dust types: SRR 6.54 (1.13-3.780) for
                                                                                         lung cancer
 Historical prospective cohort; iron        Exposure: duration of exposure               Outcome: positive association with lung and liver cancer                            Appropriate study design
 foundries (N=37); Germany; production
 workers first employed between 1950-       Mortality: data from national mortality      Lost in follow-up: 5.1%                                                             No data on exposure levels; no data
 1985 with at least one year work           statistics West Germany; diseases                                                                                                on smoking history collected,
 experience (N=17,708); reference group,    classified according to International        Standardized mortality ratios (95% confidence interval), expected/ (estimated)      however, the authors suggested that
 German general population; follow-up       Classification of Diseases                   observed:                                                                           some of the observed excess of
 mortality 1950-1993                                                                     -	malignant neoplasms: 1.24 (1.02-1.53), 881.3/1,091                               lung cancer could be explained by
                                                                                         -	trachea, bronchus, lung: 1.64 (1.24-2.23), 253.2/415                             smoking (when comparing data on
 C
   Adzersen et al. (2003)14                                                              -	liver: 3.23 (1.50-8.45), 12.4/40.1                                               smoking habits collected by others
                                                                                                                                                                             (Federal Statistical Office (general
                                                                                         Cancer mortality (all cancers) by duration of exposure and time since first         population),and Borgers and Menzel
                                                                                         exposure: only statistically significantly increased in group with less 10 years of 1984 (foundry workers); no data on
                                                                                         exposure combined with more than 30 years since first exposure: 1.36 (1.04-         other confounding factors
                                                                                         1.99), 131.4/178.5. This was mainly explained by occurrence of lung cancer
                                                                                                                                                                             Reliability 2
                                                                                         Overall, no trends in duration of employment observed
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<pre> Annexes                                                                                                                                        Iron and steel founding emissions | page 75 of 87
 Study design and population                 Data on exposure and health                 Results                                                                            Remarks and reliability
                                             assessment                                                                                                                     (annex J)
 Iron and steel foundry in a railway rolling Exposure: exposed or not exposed, based     Outcome: no association found among iron and steel workers regarding all           Appropriate study design, but limited
 stock manufacture; New Zealand; male        on longest held job title.                  cancers and lung cancer                                                            reporting on iron and steel workers
 workers for at least 3 months working in
 foundries between 1945 and 1991             Mortality: data retrieved from personnel    Standardized mortality ratio (95% confidence interval), no. observed cases:        Authors report that the prevalence
 (N=3,522 all types of jobs); reference      records; death registration records by the  All cancers                                                                        of smoking was unknown, and that it
 group, administrative workers of the same   Department of Justice; causes of death      -	exposed: 1.03 (0.59-1.67), 16 cases                                             could not be excluded as a reason
 manufacture with no exposure to any         classified according to International       -	non-exposed: 1.06 (0.89-1.24), 147 cases                                        for the increased lung cancer risk in
 contaminant                                 Classification of Diseases                  Lung cancer                                                                        the total workforce, or in different
                                                                                         -	exposed: 1.11 (0.35-2.62), 5 cases                                              occupational groups
 B
  Firth et al. (1999)50                                                                  -	non-exposed: 1.04 (0.75-1.40), 42 cases
                                                                                                                                                                            No data on exposure levels reported
                                                                                                                                                                            Reliability 2
 Nested case-control study within cohort;    Exposure: no data presented                 Outcome: positive association with bladder cancer in heaters; no association with  Appropriate study design
 steel manufacturing plant; the USA; male                                                bladder cancer in other job titles
 production workers (with 10 or more years   Mortality and other data: cases and                                                                                            Smoking habits were collected,
 of employment, N=16 bladder cancer          controls selected from company records      Study reported only on bladder cancer                                              however It was not possible to
 cases); 4 controls (N=74) selected per                                                                                                                                     adjust analyses for smoking habits
 case                                                                                    Age-adjusted odds ratios (95% confidence interval, number of exposed cases)        due to missing data; heat may have
                                                                                                                                                                            influenced the outcome for heaters
 Mallin et al. (1998)15                                                                  Job title
                                                                                         -	Heater: 21.1 (2.2-205.8), 3 cases, p<0.01 (OR, logit estimate of relative risk) Reliability 2
                                                                                         -	Labourer: 0.9 (0.3-2.8), 4 cases
                                                                                         -	Machine operator/operator learner: 1.1 (0.3-4.4), 3 cases
 Iron and steel foundries; Denmark;          Exposure: workers exposed before 1970;      Outcome: no association found                                                      Appropriate study design; limited
 N=3,056 foundry workers exposed prior to    exposed versus unexposed                                                                                                       reporting
 1970; follow-up, 1970-1992; reference                                                   Standardized mortality ratio (95% confidence interval), observed cases of death:
 group, workers employed in other            Data collection: record linking with Danish All cancers: 1.10 (0.97-1.25) 255                                                  No data on smoking habits or other
 industries (not exposed, N=43,024)          Bureau of Statistics; cause of death        Respiratory tract: 1.01 (0.80-1.25), 84                                            lifestyle factors that may have
                                             indicated according international           Digestive system: 1.15 (0.90-1.44), 74                                             influenced the outcome; no data on
 B
  Hansen (1997)51                            classification of disease (ICD)             Urinary organs: 1.31 (0.85-1.95), 25                                               exposure levels
                                                                                         Blood and lymph: 1.49 (0.97-2.19), 26 cases
                                                                                                                                                                            Reliability 2
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<pre> Annexes                                                                                                                                       Iron and steel founding emissions | page 76 of 87
 Study design and population                Data on exposure and health                  Results                                                                      Remarks and reliability
                                            assessment                                                                                                                (annex J)
 Iron, steel and non-ferrous foundries,     Exposure: duration of exposure, type of      Outcome: no association found                                                Appropriate study design
 N=20 foundries; Finland; follow-up 1950    foundry, category of monoxide and dust
 -1972; N=3,876 workers with at least 3     exposure                                     N=224 deaths recorded; loss in follow-up 1.3%                                Subgroup analyses included: age,
 months of exposure (including former and                                                                                                                             duration of exposure, foundry type,
 present workers); reference population,    Mortality: cause of death verified by death  Standardized mortality ratio (SMR, expected/observed), 47,160 person-years:  and job title
 general male population in Finland         certificates and; cause specified according  -	overall lung cancer: 1.51 (13.9/21),
                                            to international classification of diseases; -	5 yrs exposure: 1.26 (7.9/10)                                             No data on smoking habits
 C,D                       52
     Koskela et al. (1976)                  only primary cause of lung cancer included   -	> 5 yrs exposure: 1.86 (5.9/11)                                           collected, but authors report that
                                            (verified from Finnish Cancer Registry)      -	iron foundries: 2.70 (3.7/10), 7,549 person-years                         excess risk by smoking is not likely;
 Note: same cohort as described by                                                       -	steel foundries: 0.00 (1.5/0), 3,986 person-years                         no data on other confounding
 Koskela et al. (1997)53                    Selection of subjects                        Nonferrous foundries: 1.43 (0.7/1), 1,213 person-years                       factors; no data on 95% confidence
                                            Basic information from employers’ records    SMRs are not statistically significant increased compared to reference group intervals
                                            (history of foundry work); subjects traced
                                            from Population Data                         Reference population,176,468 person-years: 1.45 (42.2/61)                    Reliability 2
                                            Register of the Social Insurance Institution
 Danish national silicosis survey; iron and Exposure: years of working in foundry and    Outcome: positive association for lung and bladder cancer                    Appropriate study design
 steel foundries (N=more than 50);          type of workplace
 Denmark; male workers who had x-ray                                                     Standardized mortality ratios (95% confidence interval, expected/observed)   Common confounding factors not
 examination in 1967-1969 and 1972-1974     Data: data retrieved from Central                                                                                         taken into account, such as smoking
 (N=6,144); follow-up for disease           Population Register, Cancer Register;        Only data shown with statistically significant outcome                       habits
 development 1967 - 1985; reference         cause specified according to international
 group, general Danish population           classification of diseases                   Type of cancer                                                               Note: of the workers included in the
                                                                                         -	all malignant neoplasms: 1.09 (1.01-1.18), 594.4/647                      study, 144 were diagnosed with
 B,C,D
      Sherson et al. (1991)54                                                            -	lung cancer: 1.30 (1.12-1.51), 127.8/166                                  silicosis. Workers with silicosis did
                                                                                                                                                                      not had significant more cancer than
                                                                                         Years working in foundry                                                     the non-silicosis group
                                                                                         -	20-29 yrs (N=900):
                                                                                         -	lung cancer: 1.28 (0.93-1.76), 26.6/38                                    Reliability 2
                                                                                         -	bladder cancer: 1.72 (1.05-2.66), 11.6/20
                                                                                         - ≥ 30 yrs (N=613):
                                                                                         -	lung cancer: 1.85 (1.39-2.45), 25.9/48
                                                                                         -	bladder cancer: 1.65 (0.96-2.65), 10.3/17
                                                                                         No association between type of workplace in foundry and
                                                                                         lung and bladder cancer risk
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<pre> Annexes                                                                                                                                     Iron and steel founding emissions | page 77 of 87
 Study design and population                Data on exposure and health                 Results                                                                         Remarks and reliability
                                            assessment                                                                                                                  (annex J)
 Metal foundry industry; Denmark; male      Exposure: no data on exposure levels; no    Outcome: positive association with bladder cancer and ‘other types of malignant Appropriate study design
 moulders (identified from files of a       data on duration of exposure, job titles or neoplasms’, no association with lung cancer
 nationwide registry), N=632 (6,069 person- working area                                                                                                                No data on exposure; no data on
 years-at-risk); follow-up 10 years (1970-                                              Standardized mortality ratios (95% confidence interval, expected/observed)      other types of cancer; no
 1980); reference group, another cohort of  Mortality: Danish Bureau of Statistics (    -	cancer (all): 1.52 (1.00-2.21), 17.78/27                                     adjustments on common
 unexposed skilled workers, N=51,747        national register of deaths); diseases      -	lung cancer: 1.37 (0.63-2.60), 6.57/9                                        confounding factors, such as
 (481,642 person-years-at-risk)             classified according to International       -	bladder cancer: 8.96 (3.29-19,49), 0.67/6                                    smoking habits
                                            Classification of Diseases                  -	other malignant neoplasms: 1.14 (0.59-1.99), 10.54/12
 C,D
     Hansen (1991)55                                                                                                                                                    Reliability 2
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<pre> Annexes                                                                                                                                        Iron and steel founding emissions | page 78 of 87
 Study design and population                  Data on exposure and health                  Results                                                                           Remarks and reliability
                                              assessment                                                                                                                     (annex J)
 Automotive iron foundry; the USA; workers    Exposure: duration of exposure based on      Outcome: positive association with lung cancer in sub group only; no associations Appropriate study design
 with potential exposure for at least 6       work history; exposure levels of             with other cancer types, working area, and exposure to formaldehyde or airborne
 months between 1960-1987 (n=8,147            substances expressed as low, medium or       silica                                                                            The authors report that lung cancer
 men, N=627 women); data retrieved from       high; mean years of employment 9.5 years                                                                                       cases might be associated with
 the period 1950-1984/1989; reference                                                      Results concern men only                                                          smoking in whites, but not in
 groups, external US population               Mortality: data from Social Security                                                                                           non-whites
                                              Administration (up to 1988), Pension         Standardized mortality ratio (95% confidence interval), expected/observed:
 Additional analyses:                         Benefit Information (from 1988) and          White men (N=5,337):                                                              No measurements on exposure
 (1)	analyses of work area; workers          National Death Index; diseases classified    -	all malignant neoplasms: 0.98 (0.84-1.14), 180/177                             levels; crude analysis method of
       categorized according 6 work areas,    according to International Classification of -	lung cancer: 1.23 (0.96-1.54), 58.8/72                                         smoking habits; no data on other
       Andjelkovich et al. (1992)56           Diseases                                     -	stomach cancer: 1.67 (0.91-2.81), 8.4/14                                       confounding factors
 (2)	nested case-control study on lung                                                    Nonwhite men (2,810):
       cancer; formaldehyde exposure,         Smoking habits taken into account            -	all malignant neoplasms: 1.16 (0.99-1.34), 159.2/184                           Reliability 2
       airborne silica exposure, Andjelkovich (percentage smokers: 75.2% of exposed        -	lung cancer: 1.32 (1.02-1.67), 50.8/67
       et al. (1994)57                        workers, 72.4% of unexposed workers)         -	stomach cancer: 1.11 (0.59-1.90), 11.7/13
 (3)	subcohort; formaldehyde and silica                                                   No association observed between duration of exposure and cancer.
       exposure (cohort, N=3,929 exposed
       men, N=2,032 no exposure; follow-up                                                 Additional analysis (1)
       1950-1989), Andjelkovich et al.                                                     No associations found between type of working area and lung cancer; data
       (1995)58                                                                            probably influenced by smoking habits
 B,C,D
      Andjelkovich et al. (1990)59                                                         Additional analysis (2)
                                                                                           N=220 lung cancer deaths between 1950-1989; no associations found between
                                                                                           formaldehyde and/or airborne silica exposure and lung cancer
                                                                                           Additional analysis (3)
                                                                                           -	lung cancer: 200 cases
                                                                                           -	all causes: 2,141 cases
                                                                                           No association observed between formaldehyde exposure and lung cancer.
                                                                                           Authors observed an significant association between smoking combined with
                                                                                           silica exposure, and lung cancer
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<pre> Annexes                                                                                                                                      Iron and steel founding emissions | page 79 of 87
 Study design and population                 Data on exposure and health             Results                                                                         Remarks and reliability
                                             assessment                                                                                                              (annex J)
 Historical prospective cohort;              Exposure: mean duration of employment,  Outcome: positive association with lung and stomach cancer                      Appropriate study design
 Steel foundries (N=10), member of           9.3 years
 SCRATA (CTI); the UK; mean follow-up                                                Standardized Mortality Ratios (95% confidence interval), expected/observed      Certain groups with eastern
 period, 29.2 years; production workers      Mortality: data from National Health                                                                                    surnames were excluded due to
 (N=10,438), first employed in the period    Service Central Register or National    All cancer types: 1.19 (1.12-1.26), 948.4/1,129, p<0.001                        suspicious low overall mortality
 1946-1965, with at least one year working   Insurance records (1946-1990); diseases Lung cancer: 1.46 (1.34-1.58), 378.3/551, p<0.001
 experience; reference population, general   classified according to International   Stomach cancer: 1.34 (1.11-1.60), 92.5/1.24, p<0.01                             No data on exposure levels; no data
 population of England and Wales             Classification of Diseases                                                                                              on smoking habits or other
                                                                                     Lung cancer, specified by duration of employment history (relative risk)        confounding factors
 C,D                     60
     Sorahan et al. 1994 (earlier results    Subgroup analyses on follow-up period,  -	ever: 1.21 (0.98-1.51), N=185
 published: Fletcher and Ades (1984) and     start of working; foundry site          -	up to 5 yrs: 1.44 (1.13-1.82), N=129                                         Reliability 2
 Sorahan et al. 1989))61                                                             - ≥ 15 yrs: 1.26 (0.95-1.67), N=80
 Nested case-control in a cohort described   Exposure: based on history data (rough  Outcome: positive association for lung cancer; no association with type of work Appropriate study design
 by Koskela et al. (1976); iron foundries    classification by type of work, and by  and with PAH exposure
 (N=13); Finland; male workers with at least current exposure to PAH (low, some and                                                                                  No data on 95% confidence interval;
 one year of employment in foundry           heavy exposure)                         Study based on the assumption that an association between iron foundry work     no adjustments for well-known
 (N=3,425); registers used from 1918-                                                and lung cancer exists. Goal is to assess the hazard                            confounding factors, such as
 1972, cases included up to 1976;            Mortality: see Koskela et al. (1976)37                                                                                  smoking habits (Internal contrast
 reference group, general male population    Data on smoking habits included (57% of N=51 lung cancer cases                                                          in risk not likely
 in Finland                                  works smoked)                           N=544 death cases (all causes)                                                  to be caused by
                                                                                                                                                                     smoking.)
 Tola et al. (1979)18; data included from                                            Lung cancer, proportional mortality:
 cohort by Koskela et al. (1976)52                                                   1.44 (35.3 expected cases, 51 observed cases), p<0.05                           Reliability 2
                                                                                     No clear associations between type of work or current exposure to PAH and lung
                                                                                     cancer, except for:
                                                                                     -	type of work (casters): risk ratio 4.6 (1.9 expected/7 observed), p<0.01
                                                                                     -	Heavy PAH exposure: risk ratio 1.71 (66 controls/ 29 cases)
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<pre> Annexes                                                                                                                                           Iron and steel founding emissions | page 80 of 87
 Study design and population                   Data on exposure and health                  Results                                                                          Remarks and reliability
                                               assessment                                                                                                                    (annex J)
 Iron, steel and non-ferrous foundries,        Exposure: exposure levels: low, medium       Outcome: positive association for certain cancer types                           Appropriate study design
 N=22 iron and steel foundries; Finland;       and high depending on physical job
 follow-up 1950 -1987; N=6,415 workers         demands; data on duration of employment      Standardized mortality ratio (95% confidence interval, expected/observed)        No analyses by duration of
 with at least 3 months of exposure            available                                                                                                                     exposure or job demands
 (including former and present workers);                                                    Cancer development (134,660 person-years):                                       presented; no data on common
 reference population, general male            Mortality and other data: cause of death     -	all types of tumours: 1.29 (1.13-1.47), 184.4/238, p<0.001                    confounding factors, such as
 population in Finland                         verified by death certificates and           -	lung cancer: 1.43 (1.17-1.74), 71.3/102, p<0.001                              smoking habits
                                               Population Information System; cause         -	cancer digestive organs: 1.50 (1.14-1.94), 39.3/59, p<0.01
 A
  Koskela et al. (1997)53                      specified according to international                                                                                          Reliability 2
                                               classification of diseases; questionnaires
 Note: same cohort as described by             to current and former workers for
 Koskela et al. (1976)52                       additional information
                                               Selection of subjects
                                               Basic information from employers’ records
                                               (history of foundry work); subjects traced
                                               from Population Data
                                               Register of the Social Insurance Institution
 Gray iron foundry of an industrial plant; the Exposure: duration of exposure (ever         Outcome: study is too limited to draw conclusions                                Appropriate study design, but limited
 USA; male workers for at least one year       employed (N=2,861), employed for > 5                                                                                          reporting
 between 1938 and 1967 (N=2,861);              years (N=867))                               Standardized mortality ratios (expected/observed), white/nonwhite men:
 reference group, general US male                                                           ≥ 1 month employment                                                             No exposure levels determined; no
 population                                    Mortality: data retrieved from company       -	cancer (all types): 1.11 (49.4/55), 0.88 (39.6/35)                            data on confounding factors, such
                                               personnel records, Social Security           ≥ 5 years employment                                                             as smoking habits; limited data
 B,D
    Decoufle and Wood 197962                   Administration, and death certificates;      -	cancer (all types): 1.13 (20.4/23), 1.05 (17.2/18)                            reported on statistical analyses and
                                               diseases classified according to             Most cancers were observed in the stomach and respiratory system.                standardized mortality ratios
                                               International Classification of Diseases
                                                                                            No statistically significant associations found between being exposed and cancer Reliability 3
                                                                                            development
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<pre> Annexes                                                                                                                                    Iron and steel founding emissions | page 81 of 87
 Study design and population                 Data on exposure and health                Results                                                                   Remarks and reliability
                                             assessment                                                                                                           (annex J)
 Cohort study; the USA; 2,167 male           Exposure: no data                          Standardized mortality ratio (SMR), observed/expected deaths              Limitations in study design
 workers at seven steel foundries; period of
 employment 1953; period of follow-up        Data collection: deaths confirmed by death Lung cancer:                                                              Selection of reference group is not
 1953 -1970; reference group, total          certificates; cause of death indicated     A: 1.14, 20/17.7                                                          common (all steelworkers in the
 steelworker population in the same plants   according international classification of  B: 1.00, 34/34                                                            same plant instead of
                                             disease (ICD)                              C: 1.16, 23/20.1                                                          non-steelworkers in the same
 C,D
     Breslin (1979)63                                                                   Genito-urinary cancer:                                                    plants, or in the general population);
                                             Subcohorts:                                A: 1.75, 12/7.1                                                           no data on smoking habits
                                             A: first job in 1953 was in the foundry    B: 1.28, 17/13.6
                                             (N=1,173)                                  C: 1.62, 14/8.9                                                           Reliability 3
                                             B: ever employed in the foundry through    All cancers:
                                             1953 (N=2,167)                             A: 1.20*, 71/60.3
                                             C: employed in the foundry for at least 5  B: 1.08, 123/115.2
                                             years through 1953 (N=958)                 C: 1.16, 80/70.3
                                                                                        * statistically significant, p≤0.05
                                                                                        Data as reported by Bosetti et al.
                                                                                        (95% confidence interval), complete cohort:
                                                                                        Lung cancer:
                                                                                        SMR 1.00 (0.7-1.4), 34 death cases
                                                                                        Bladder cancer:
                                                                                        SMR 1.00 (0.2-2.8), 3 death cases
                                                                                        Kidney cancer:
                                                                                        1.6 (0.4-4.1), 4 death cases
 Proportional mortality study; member of     Exposure: workers categorized according    Outcome: positive association with lung cancer in age                     Small study
 the Iron Moulders Society of South Africa   job title and age                          group higher than 65 years old
 (IMS-SA); South Africa; N=578 deaths                                                                                                                             Type of study design is notoriously
 recorded between 1961-1983; reference       Mortality: data retrieved from IMS-SA and  Proportional mortality ratios (expected/observed)                         prone to bias; according to the
 group, deaths in general white male         South African national death records;      -	age 20-64 yrs (N=372):                                                 authors smoking cannot fully explain
 population                                  diseases classified according to           -	all cancers: 0.75 (53.7/40), p=0.03                                    increased mortality ratios (data not
                                             International Classification of Diseases   -	lung cancer: 0.84 (15.48/13), p=0.31                                   presented)
 Sitas et al. (1989)16                                                                  - age ≥ 65 yrs (N=206):
                                                                                        -	all cancers: 0.91 (36.12/33), p=0.34                                   Reliability 4
                                                                                        -	lung cancer: 1.71 (8.75/15), p=0.03
80          Health Council of the Netherlands | No. 2020/02                                                                                                2                                           82
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<pre> Annexes                                                                                                                                Iron and steel founding emissions | page 82 of 87
 Study design and population              Data on exposure and health               Results                                                                   Remarks and reliability
                                          assessment                                                                                                          (annex J)
 Proportional mortality study; members of Exposure: no information given            Outcome: positive association with lung cancer
 the International Moulders and Allied                                                                                                                        Data on proportional mortality ratios
 Workers Union (IMAW); the USA; N=2,990   Mortality: data obtained from IMAW;       Proportional mortality ratio (expected/observed):                         are prone to bias; no data on 95%
 death cases between 1971-1975;           diseases classified according to          All cancers:                                                              confidence intervals; data not
 reference group, deaths in general US    International Classification of Diseases  -	White workers (N=2,651): 1.10 (497.65/545), p<0.05                     adjusted for common confounding
 male population                                                                    -	Nonwhite workers (N=339): 1.24 (69.29/86), p<0.05                      factors, such as smoking habits
                                          Smoking habits: authors expect limited    Lung cancer:
                           64
 Egan-Baum et al. (1981)                  influence on results since differences in -	white workers: 1.44 (155.17/224), p<0.01                               Reliability 4
                                          smoking habits between exposed and        -	nonwhite workers: 1.76 (22.10/39), p<0.01
                                          non-exposed subjects is considered small  Other types of cancer not associated with exposure in foundry
81        Health Council of the Netherlands | No. 2020/02                                                                                              2                                          83
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<pre> Annexes                                                                                                                                       Iron and steel founding emissions | page 83 of 87
 L          epidemiology: case-control studies
 Study design and population                 Data on exposure and health                  Results                                                                      Remarks and reliability
                                             assessment                                                                                                                (annex C)
 Case-control study on worker population in  Exposure: no data on exposure levels;        Outcome: positive association found for lung cancer when working in blast    Appropriate study design, small
 one large iron and steel foundry; Asturias, categorisation by production process.        furnace area; no associations found for lung cancer in other work areas      study
 Spain; male workers, cases were identified
 by job records and cancer registries        Data collection: Tumor Registry of the       Odds ratios (95% confidence interval, cases/controls) of lung cancer (data   Adjusted for smoking and age
 (period 1952-1995), N=144 lung cancer       General Hospital of Asturias and Tumour      adjusted for smoking and age)
 cases; N=558 age-matched controls           Registry of Asturias; diseases classified                                                                                 No data on other types of cancer;
 (workers) not having lung cancer            according to International Classification of Ever employed in:                                                            no data on exposure levels
                                             Diseases; data on smoking habits (cases/     -	foundry: 1.64 (0.69-3.91), 10/24
 RodrÍguez et al. (2000)22                   controls: N=131/436 ever smokers,            -	blast furnace: 2.55 (1.25-5.21), 16/36                                    Reliability 2
                                             N=1/108 never smoker
                                                                                          By longest held job in:
                                                                                          -foundry: 1.91 (0.74-4.93), 9/18
                                                                                          -blast furnace: 2.11 (0.78-5.73), 7/17
 Population-based study design; area of      Data collection: categorization based on     Outcome: no association found for bladder cancer                             Appropriate study design
 former coal, iron, and steel industries;    type of work; questionnaire on occupations
 Germany; cases and controls obtained        performed and smoking habits;                Odds ratio (95% confidence interval, cases/controls) for urothelial cancer   Adjusted for smoking; no data on
 from three hospitals in Eastern Ruhr area                                                (adjusted for smoking habits)                                                other types of cancer
 (diagnosed in period 1984-1988; cases       Smoking habits:
 are male workers who were employed for      -	Cases: 58.3% smokers, 12.2%               Iron and steel foundry workers                                               Reliability 2
 at least 10 years in one of the three          ex-smokers                                1.1 (0.69-1.69), 8/3, p=0.735
 industries, prior to investigation          -	Controls: 35.3% smokers, 9.7%
                                                ex-smokers
 Golka et al., (1998)26
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<pre> Annexes                                                                                                                                      Iron and steel founding emissions | page 84 of 87
 Study design and population                Data on exposure and health                  Results                                                                          Remarks and reliability
                                            assessment                                                                                                                    (annex C)
 Case-control study on worker population in Exposure: no data on exposure levels;        Outcome: positive association with lung and stomach cancer                       Appropriate study design
 a large iron-steel complex; Anshan, China; data retrieved (personnel records) on
 cases selected from active and retired     duration of exposure and job activities/     Odds ratios (95% confidence interval, cases/controls) of lung and stomach cancer Adjustments made for smoking and
 workers which were diagnosed with cancer   working areas                                (data adjusted smoking and age)                                                  age, however no smoking data
 in the period 1987-1993 (primary lung                                                                                                                                    presented
 cancer) and 1989-1993 (stomach cancer);    Cancer data collection: municipal cancer     Lung cancer (foundry workers; 172 cases, 411 controls)
 N=610 cases of primary lung cancer,        registry; medical records from hospitals;    -	ever worked: 1.8 (1.1-2.8), 48/47                                             Reliability 2
 N=293 cases of stomach cancer in           interviews of cases, controls or next of kin -	worked < 15 yrs: 2.7 (1.3-5.7), 21/15
 employees with at least 10 years of                                                     - worked ≥ 15 yrs: 1.4 (0.8-2.4), 27/32
 employment
                                                                                         Stomach cancer (foundry workers; 91 cases, 411 controls):
 Xu et al. (1996)23, 24                                                                  -	ever worked: 2.0 (1.1-3.5), 30/47
                                                                                         -	worked < 15 yrs: 3.9 (1.7-9.0), 15/14
                                                                                         - worked ≥ 15 yrs: 1.2 (0.6-2.5), 15/33
 Population-based study design; foundries;  Data collection: Next of-kin interviewed to  Outcome: positive association for lung cancer in longest exposed worker          Appropriate study design, small
 Poland; N=901 deaths from lung cancer in   obtain a residential, occupational and       population                                                                       study
 1980-1985 among males in Crakow;           smoking history.
 N=875 controls selected among men dying                                                 Response rate: 70.7% (cases) and 73.5% (controls)                                Adjustment for age, smoking, other
 from causes other than respiratory cancer  Disease verification: data retrieved from                                                                                     occupational exposures as potential
 or chronic respiratory disease, frequency  death certificates from Crakow death         N=106 cases and 72 references in steel and iron foundries                        confounders
 matched to the cases with regard to age    register
                                                                                         Simultaneous relative risk (95% confidence interval, cases/control)              No data on exposure levels; no data
 Becher et al. (1989)20                                                                                                                                                   on other types of cancer
                                                                                         Lung cancer
                                                                                         Years of employment in foundry                                                   Reliability 2
                                                                                         -	1-20 yrs or unknown: 1.28 (0.75-2.20)
                                                                                         -	20-30 years: 1.58 (0.94-2.66)
                                                                                         -	>30 years: 2.66 (1.31-5.42)
                                                                                         No data on other types of cancer; no data on cases/controls
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<pre> Annexes                                                                                                                                         Iron and steel founding emissions | page 85 of 87
 Study design and population                Data on exposure and health                   Results                                                                             Remarks and reliability
                                            assessment                                                                                                                        (annex C)
 Population-based study design; steel       Data collection: Face-to face interview with Outcome: positive association found for lung cancer                                  Appropriate study design, small
 industry or foundry workers; eastern       next-of-kin, recording occupational history,                                                                                      study
 Pennsylvania, the USA; N=335 white men     smoking history and residential history       Response rate 94%
 who died from 1974 to 1977 from lung                                                                                                                                         Adjustment for smoking and age as
 cancer; controls (N=332) men, matched to   Disease verification: pathologically verified Odds ratios (95% confidence interval, cases/control)                                potential confounders
 the cases by race, age, sex, county and    primary lung cancer; data retrieved from
 year of death, and free from respiratory   population mortality registers                Lung cancer                                                                         No data on exposure levels or
 cancer or chronic respiratory disease                                                    Employed in steel industry (“usual industry”): 2.2 (1.5-3.3), 80/43                 employment duration; no data on
                                                                                          Employed as foundry worker, mold maker (6 cases and 1 control):                     other types of cancer
 Blot et al. (1983)21                                                                     7.1 (1.2-42.3), 6/1
                                                                                          Smoking did not influence outcomes                                                  Reliability 2
 Study is part of Occupational Cancer       Exposure: No data on exposure levels;         Outcome: positive association found for brain cancer; no trend for years of         Appropriate study design
 Monitoring (OCCAM) project; Italy, area of duration of exposure divided into three       employment
 Umbria (Perugia and Terni); focus on iron  groups:                                                                                                                           No data on other types of cancer;
 and steel foundry workers; cases selected  0-4 yrs                                       Odds ratios (90% confidence interval, cases/controls) of brain cancer (adjusted for 90% confidence interval instead of
 from male workers occupied for at least 1  5-9 yrs                                       age and sex)                                                                        the usual 95% confidence interval,
 year since 1974, aged between 35-74        ≥ 10 yrs                                                                                                                          wide spread of confidence interval
 years at diagnosis (N=13,589), and                                                       Iron and steel foundry in Terni:                                                    noted; no data on smoking habits
 controls from same population matched for  Data on cancer: Umbria Regional Cancer        -	overall: 9.59 (2.76-33.34), 16 cases, p=0.003
 sex, province of residence and 5-y age     Registry (data retrieved from period          Duration of employment:                                                             Reliability 2
 class (N=44,474)                           2002-2008)                                    -	0-4 yrs: 1.00 (-), 2 cases
                                                                                          -	5-9 yrs: 13.64 (3.27-56.96), 4 cases, p=0.003
 Oddone et al. (2014)65                                                                   - ≥10 years: 8.58 (2.40-30.75), 10 cases, p=0.006
 Population-based study design; area of     Data collection: Job and industry recorded    Outcome: no association found for lung cancer                                       Appropriate study design, small
 two steel producing plants, of which one   from the death certificates; job histories                                                                                        study
 has a substantial foundry operation;       obtained from employers                       Relative lung cancer risks (95% confidence interval, number of cases)
 Canada; subjects (N=967) were men who                                                                                                                                        No smoking
 died of lung cancer from 1979-1983         Disease verification: not reported            -	Steelworkers Sault St-Marie: 0.85 (0.58-1.23), 73 cases                          Adjustment; no data on exposure
 (Hamilton and Sault                                                                      -	Steelworkers Hamilton: 1.10 (0.89-1.37), 145 cases                               levels; no data on other types of
 Ste-Marie, Ontario); controls were men                                                   (Adjusted for age and time period)                                                  cancer
 who died from other causes (N=2,827)                                                     -	Foundry work for >5 years (Hamilton): 1.94 (0.75-5.2), 12 cases
                                                                                                                                                                              Reliability 2
 Finkelstein (1994)25                                                                     No association between work in foundries and lung cancer risk
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<pre>                                                                                              Iron and steel founding emissions | page 86 of 87
 The Committee
 The membership of the Subcommittee on Classifying Carcinogenic Substances for the evaluation
 of the carcinogenicity and genotoxicity of iron and steel founding emissions
 •    H.P.J. te Riele, Professor of molecular biology, VU University Amsterdam,
      and Netherlands Cancer Institute, Amsterdam, chairman
 •    P.J. Boogaard, Professor of environmental health and human biomonitoring,
      Wageningen University and Research Centre, and toxicologist,
      SHELL International BV, The Hague
 •    M.J.M. Nivard, Molecular biologist and genetic toxicologist,
      Leiden University Medical Center, Leiden
 •    E. de Rijk, Toxicologic pathologist, Charles River Laboratories, ‘s Hertogenbosch
 •    J.J. Vlaanderen, Epidemiologist, Institute for Risk Assessment Sciences, Utrecht
 •    J. van Benthem, Genetic toxicologist, RIVM, Bilthoven, structurally consulted expert
 Observer
 •    M. Woutersen, Bureau REACH, RIVM, Bilthoven
 Scientific secretary
 •    J.M. Rijnkels, The Health Council of the Netherlands, The Hague
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<pre> The Health Council of the Netherlands, established in 1902, is an independent scientific advisory body. Its remit is “to advise the government and
 Parliament on the current level of knowledge with respect to public health issues and health (services) research...” (Section 22, Health Act).
 The Health Council receives most requests for advice from the Ministers of Health, Welfare and Sport, Infrastructure and Water Management, Social
 Affairs and Employment, and Agriculture, Nature and Food Quality. The Council can publish advisory reports on its own initiative. It usually does this in
 order to ask attention for developments or trends that are thought to be relevant to government policy.
 Most Health Council reports are prepared by multidisciplinary committees of Dutch or, sometimes, foreign experts, appointed in a personal capacity.
 The reports are available to the public.
 This publiation can be downloaded from www.healthcouncil.nl.
 Preferred citation:
 Health Council of the Netherlands. Iron and steel founding emissions
 The Hague: Health Council of the Netherlands, 2020; publication no. 2020/02.
 All rights reserved
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