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Beskæftigelsesudvalget 2019-20
BEU Alm.del Bilag 101
Offentligt

Asbestos

Scientific basis for

setting a health-based

occupational

exposure limit

Niels Hadrup, Anne Thoustrup Saber, Nicklas Raun Jacobsen and Ulla Vogel

BEU, Alm.del - 2019-20 - Bilag 101: Orientering om NFA’s forslag til grænseværdier for fem kemiske stoffer, fra beskæftigelsesministeren BEU, Alm.del - 2019-20 - Bilag 101: Orientering om NFA’s forslag til grænseværdier for fem kemiske stoffer, fra beskæftigelsesministeren

SBESTOS

: S

CIENTIFIC BASIS FOR SETTING A HEALTH

BASED OCCUPATIONAL EXPOSURE LIMIT

Niels Hadrup

Anne Thoustrup Saber

Nicklas Raun Jacobsen

Ulla Vogel

National Research Centre for the Working Environment, 2019

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OREWORD

The Danish Working Environment Authority has asked the National Research Centre for the

Working Environment (NFA) to review the scientific evidence underlying a health-based

occupational exposure limit for asbestos.

The purpose of the present report is to suggest a health-based occupational exposure limit for

asbestos.

The working group wishes to thank Chief Toxicologist Poul Bo Larsen, DHI, Denmark, for

reviewing the report.

Copenhagen, June 2019

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XECUTIVE

UMMARY

Asbestos are silicate minerals containing elements such as Al, Ca, Mg and Fe. Asbestos encompass

6 different silicates, of which one, chrysotile has a serpentine (leaf like) structure and the other 5

have an amphibole structure (a chain-like crystalline structure). In Denmark, asbestos was

previously used in products such as building materials and brake pads. Asbestos was banned in

new products in 1987, but exposure still occurs due to its presence in materials installed prior to

the ban.

In this report, a working group at the NFA has reviewed scientific data relevant to assessing the

hazard of asbestos, i.e. human studies

toxicokinetics, animal studies, mechanisms of toxicity,

previous hazard and risk assessments of asbestos, and the scientific basis for setting an

occupational exposure limit (OEL). Finally the working group suggests a health-based OEL for

asbestos. The focus of this report is occupational exposure by inhalation. The present working

group evaluated the relevant literature on asbestos from both epidemiological studies and

pulmonary exposure in animal studies. Cell culture studies were only used for the description and

clarification of mechanisms and modes of action.

Concerning its absorption and distribution, asbestos has been fund in lungs and other organs of

exposed workers. In addition, asbestos has been fund in foetal tissues of exposed mothers. In

some workers all types of asbestos were found in the lungs, probably reflecting that the various

types are cross-contaminated by each other. Following inhalation exposure of animals, asbestos

was observed in a range of pulmonary structures and cell types as well as in the lymphatic and

vascular compartments. In the lungs of rats, chrysotile has been described to break into smaller

fibres, be partly bio-soluble and have a considerably lower persistence in comparison to amphibole

asbestos types such as tremolite and crocidolite. The difference in elimination of the serpentine

chrysotile and the amphibole asbestos types likely reflects that they break up in different ways

inside the mammalian body.

The main asbestos induced diseases include cancer but also the non-cancer disease of asbestosis

involving long term inflammation and scarring of the lungs. In spite of its importance, the current

working group has assessed that asbestosis does not represent the critical effect endpoint for

hazard assessment. This is based on the likelihood of a threshold mechanism of action in this

disease – something that is in contrast to the mechanism of action of asbestos in carcinogenesis.

In the assessment of the presence of a carcinogenic threshold we assessed genotoxicity data. We

found some evidence from animal experiments that asbestos has cytogenic effects – in terms of

increased frequency of chromosome aberrations and sister chromatid exchanges. Thus, a genotoxic

effect at the chromosome level is suggested. Furthermore, a number of studies have shown that

asbestos fibres have mutagenic effects: amosite induced mutations in an

in vivo

mammalian

mutagenicity assays, in one positive study. For crocidolite, there are three positive studies and one

negative study. Overall, there is

in vivo

evidence for mutagenic effects of asbestos fibres. The

current working group recommends to comply with the European Chemicals Agency (ECHA),

who in the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) R8

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(ECHA, 2012) states the following: “Unless

a threshold mechanism of action is clearly demonstrated, it is

generally considered prudent to assume that thresholds cannot be identified in relation to mutagenicity,

genotoxicity, and genotoxic carcinogenicity, although a dose-response relationship may be shown under

experimental conditions”.

Based on this, the current working group recommends that asbestos fibres

are hazard assessed using a numerical risk assessment based on a linear approach and thus based

on a notion that there is no threshold.

There is evidence from studies on humans that asbestos causes cancer of the lung, pleural and

peritoneal mesothelioma, gastrointestinal-tract cancers, cancer of the larynx, and cancer of the

ovary. In animals, the inhalation of asbestos induced carcinogenicity at a mass concentration of 2

mg/m

, and above. When presenting the data as fibre concentration, carcinogenicity has been

reported already at 108 fibres/mL.

Risk assessments by

The Dutch Expert Committee on Occupational Safety

(DECOS, 2010) and by

The

French Agency for Food, Environmental and Occupational Health & Safety

(Afsset, 2008), lead to

practically identical risk estimates for excess human lung cancer risk mortality in relation to

asbestos exposure. Taking both assessments together, a mean 8h-Time-weighted average (TWA)

asbestos exposure over 40 working years of about 0.0001 fibres/mL would lead to an excess lung

cancer mortality rate of 1 x 10

-5

. Our calculations based on the K

value for lung cancer set by

DECOS based on a) DECOS’ selected 4 studies based on their own quality criteria; and b) the

DECOS’ K

value for their initially selected 18 studies - were in line with the number on lung

cancer given by DECOS. Since smoking is not a risk factor for mesothelioma, the current working

group recommends using the risk estimates by DECOS for asbestos-induced mesothelioma and

their combined risk estimate for lung cancer and mesothelioma. In addition, the current working

group recommends the use of DECOS’ risk estimate for amphiboles to determine an OEL for all

asbestos types. Risk estimates based on animal data did not indicate that animal studies would

provide a lower risk estimate for lung cancer, also there is sufficient human data to base a hazard

assessment upon. The current working group therefore recommends using human data in setting

risk levels for a health-based OEL.

The current working group suggests that the following

exposure levels leading to excess cancer risk

are

used:

Excess cancer incidence

of lung cancer or

mesothelioma

1:1000

1:10 000

1:100 000

Risk levels (8h-TWA) based on a meta-analysis

conducted by DECOS on Human studies of

mesothelioma and lung cancer combined – calculated

based on exposure to amphibole asbestos

0.01 fibres/mL

0.001 fibres/mL

0.0001 fibres/mL

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ANSK SAMMENFATNING

Asbest består af silikatmineraler, der indeholder grundstoffer såsom Al, Ca, Mg og Fe. Asbest

består af 6 forskellige silikater, hvoraf én, chrysotil, har en serpentin-(bladlignende)-struktur, og de

andre 5 har en amfibolstruktur (en kædelignende krystallinsk struktur). I Danmark blev asbest

tidligere brugt i fx byggematerialer og bremseklodser. Asbest blev fra 1987 forbudt i nye

produkter, men der er stadig eksponering fra produkter taget i brug før dette årstal.

I denne rapport vurderer en arbejdsgruppe ved Det Nationale Forskningscenter for Arbejdsmiljø

(NFA) data, der er relevante for at vurdere faren ved udsættelse for asbest, dvs. humane studier,

toksikokinetik, dyreforsøg, toksicitetsmekanismer, tidligere farevurderinger af asbest samt det

videnskabelige grundlag for fastlæggelse af en grænseværdi. Endeligt opsummeres og foreslås en

helbredsbaseret grænseværdi for asbest i arbejdsmiljøet. Fokus er i denne rapport på

erhvervsmæssig eksponering ved indånding. Den nærværende arbejdsgruppe evaluerede den

relevante litteratur om asbest fra både epidemiologiske undersøgelser og inhalationsforsøg med

dyr. Celleforsøg er kun blevet evalueret, hvor de var nødvendige for at afklare og beskrive asbests

virkningsmekanismer.

Absorption og fordeling af asbest er hos arbejdere påvist i lungerne samt andre organer. Asbest er

blevet påvist i fostre fra eksponerede mødre. Samtlige asbest-typer er blevet påvist i lungerne hos

nogle arbejdere. Dette afspejler sandsynligvis, at de forskellige typer optræder som forureninger af

hinanden. I dyreforsøg er asbest efter indånding blevet målt i en række lungestrukturer og –

celletyper, samt i lymfe- og kar-væv. I lungerne hos rotter er det blevet beskrevet at chrysotil

knækker til mindre fibre; og at chrysotil er mindre bio-persistent i sammenligning med amfibol-

asbesttyper som tremolite og crocidolit. Denne forskel skyldes sandsynligvis forskellig

nedbrydningshastighed i kroppen.

De vigtigste asbest-inducerede sygdomme er kræft og asbestose. Asbestose er en sygdom med

vedvarende inflammation og fibrose i lungerne. Den nuværende arbejdsgruppe har vurderet, at

asbestose ikke repræsenterer det kritiske effekt-endepunkt til farevurdering. Dette er baseret på, at

der sandsynligvis er en tærskelmekanisme for udvikling af denne sygdom.

I vores vurdering af om asbestinduceret kræft har en tærskelmekanisme har vi set på

genotoksicitets-data. Der er data fra dyreforsøg, der peger på, at asbest udviser genotoksisk effekt

på kromosomniveau: Asbest har virkninger i form af forhøjede kromosomaberrationer og såkaldte

sister chromatid exchanges.

Desuden har en række undersøgelser vist, at asbestfibre har mutagene

effekter: Amosit-inducerede mutationer i et mutagenicitets-studie; for crocidolit var der effekt i tre

studier, mens et studie var negativt. Samlet set peger data fra dyreforsøg på en mutagen virkning

af asbestfibre. Den nuværende arbejdsgruppe anbefaler at følge ECHA’s REACH-R8 retningslinje

(ECHA, 2012), som anbefaler at: medmindre en tærskelværdi er klart påvist, anses det generelt for

mest fornuftigt at antage, at en tærskel ikke kan identificeres i relation til mutagenicitet,

genotoksicitet, og genotoksisk carcinogenicitet. På baggrund heraf anbefaler den nærværende

arbejdsgruppe, at asbestfibre farevurderes ved brug af en såkaldt lineær udregningsmetode og

altså baseret på en antagelse af, at asbest ikke har nogen tærskel i sin kræft-inducerende effekt.

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Der er betydelig evidens for, at asbest kan inducere lungekræft, mesoteliom (lungehindekræft),

mave-tarmkræft samt kræft i strubehoved og i æggestokken. I dyreforsøg inducerer asbest kræft

ved inhalationen af massekoncentrationer på 2 mg/m

og derover; eller ved en koncentration på

108 fibre/mL og derover.

Farevurderinger fra

The Dutch Expert Committee on Occupational Safety

(DECOS, 2010) og fra

The

French Agency for Food, Environmental and Occupational Health & Safety

(Afsset, 2008), giver næsten

identiske vurderinger for overskydende kræftrisikoniveauer ved asbesteksponering. Hvis man

tager begge vurderinger i betragtning, vil en gennemsnitlig

8-h-TWA

asbesteksponering over 40

arbejdsår på 0,0001 fibre/mL medføre en overskydende lungekræft- og mesoteliom-dødelighed på

1x10

-5

. Arbejdsgruppens egne beregninger baseret på K

-værdien for lungekræft fastsat af DECOS

baseret på enten: a) DECOS’ værdi for 4 studier udvalgt vha. deres egne kvalitetskriterier; eller: b)

DECOS’ K

-værdi for 18 brutto-udvalgte undersøgelser - var i overensstemmelse med DECOS’ tal

for lungekræft. Eftersom rygning ikke er en kendt risikofaktor for udvikling af mesoteliom

anbefaler Arbejdsgruppen at bruge DECOS’ risikoestimat for asbest-induceret mesoteliom; samt

DECOS’ kombinerede risikoestimat for mesoteliom og lungekræft. Samtidigt anbefaler

Arbejdsgruppen at bruge DECOS’ risikoestimat for amfibol asbest til at sætte en grænseværdi for

alle asbesttyper. Vores farevurdering baseret på data fra dyreforsøg, viser at denne type forsøg

ikke giver et lavere risikoestimat for lungekræft. Desuden er der tilstrækkelig humane data til at

foretage en farevurdering. Den nærværende arbejdsgruppe anbefaler derfor at anvende humane

data til at fastsætte fareniveauer for en sundhedsbaseret grænseværdi.

Den nuværende arbejdsgruppe anbefaler at følgende overskydende kræftrisikoniveauer anvendes:

Overskydende

lungekræft- og

mesoteliom-incidens

1:1000

1:10 000

1:100 000

Risikoniveauer (8h-TWA) baseret på meta-analyser

udført af DECOS på human mesoteliom samt

lungekræft – baseret på eksponering til amfibol asbest

0,01 fibre/mL

0,001 fibre/mL

0,0001 fibre/mL

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CKNOWLEDGEMENTS

We wish to thank researchers Nicklas Mønster Sahlgren, for help in drawing molecular structures,

and Camilla Sandal Sejbæk for valuable advice concerning some epidemiological studies.

Moreover, librarians Elizabeth Bengtsen and Rikke Nilsson are thanked for their assistance in

literature searches and retrieval of literature.

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ONTENTS

Foreword ................................................................................................................................... 3

Executive Summary .................................................................................................................... 4

Dansk sammenfatning ............................................................................................................... 6

Acknowledgements .................................................................................................................... 8

Contents .................................................................................................................................... 9

Abbreviations........................................................................................................................... 10

Recommendation from the working group of the National Research Centre for the Working

Environment ............................................................................................................................ 12

Recommendation executive summary ...................................................................................... 13

Derived Limit Values /Carcinogenic Risk Assessment ......................................................................... 13

Recommendation on occupational exposure limits for asbestos ................................................ 14

1. Chemical agent identification and physico-chemical properties...................................................... 14

2. EU harmonised classification and labelling .................................................................................... 21

3. Chemical agent and scope of legislation ........................................................................................ 21

4. Existing occupational exposure limits ............................................................................................ 22

5. Occurrence, use and occupational exposure .................................................................................. 25

5.1. Occurrence and use .......................................................................................................................................... 25

5.2. Production and use information ....................................................................................................................... 25

5.3. Occupational exposure ..................................................................................................................................... 25

5.4. Routes of exposure and uptake ........................................................................................................................ 26

6. Monitoring exposure .................................................................................................................... 26

6.1 Monitoring airborne asbestos in the workplace ................................................................................................ 26

6.2 Biomonitoring methods for asbestos in the workplace ..................................................................................... 27

7. Health effects ............................................................................................................................... 27

7.1. Toxicokinetics (absorption, distribution, metabolism, excretion) .................................................................... 27

7.2. Acute toxicity .................................................................................................................................................... 34

7.3. Specific Target Organ Toxicity/Repeated Exposure .......................................................................................... 35

7.3.3. In vitro data .................................................................................................................................................... 40

7.4. Irritancy and corrosivity .................................................................................................................................... 40

7.4.2. Animal data .................................................................................................................................................... 40

7.5. Sensitisation ...................................................................................................................................................... 40

7.6. Genotoxicity ...................................................................................................................................................... 40

7.7. Carcinogenicity .................................................................................................................................................. 44

7.7.1. Human data (covering the period up to 2012 - based on IARC 2012) ........................................................... 44

7.7.2. Human data after IARC 2012 ......................................................................................................................... 48

7.8. Reproductive toxicity ........................................................................................................................................ 82

7.9. Mode of action considerations ......................................................................................................................... 83

7.10. Lack of specific scientific information ............................................................................................................. 84

8. Groups at extra risk ...................................................................................................................... 84

References ............................................................................................................................... 85

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BBREVIATIONS

8-oxo-dGua 8-Oxo-2'-deoxyguanosine

Afsset

Agence française de sécurité sanitaire de l’environnement et du travail / French

Agency for Food, Environmental and Occupational Health & Safety

AAG

Anthophyllite, actinolite and glaucophane

ADME

Absorption, distribution, metabolism and excretion

ALARA

As low as reasonable achievable

ANSES

French Agency for Food, Environmental and Occupational Health

ATSDR

Agency for Toxic Substances and Disease Registry

BAL

Broncho-alveolar lavage

BAuA

German Federal Institute for Occupational Safety and Health

BLV

Biological limit value

Body weight

CAS

Chemical Abstract Service

CI:

Confidence interval

Cubic centimetre; in the current document, Cm

and mL, although equal, are used

interchangeably

DECOS

Dutch Expert Committee on Occupational Safety

DGUV/IFA Institut für Arbeitsschutz der Deutschen Gesetzlichen Unfallversicherung

DHI

Dansk Hydraulisk Institut

DGS

Directorate General for Health

DGT

Directorate General for Work

DPPR

Directorate General for Pollution and Risk Prevention

ECHA

European Chemicals Agency

EEC

European Economic Community

IARC

International Agency for Research on Cancer

IER

Increased excess risk

IOM

Institute of Medicine

L/D

Length-to-diameter ratio

LDH

Lactat dehydrogenase

LNT model Linear no-threshold model

LOAEC

Lowest observed adverse effect concentration

mRNA

Messenger RNA

NFA

National Research Centre for the Working Environment

NIEHS

National Institute of Environmental Health Sciences

NOAEC

No observed adverse effect concentration

NOAEL

No observed adverse effect level

NTP

National Toxicology Program

OEL

Occupational exposure limit

PCM

Phase contrast microscopy

REACH

Registration, Evaluation, Authorisation

and Restriction

of Chemicals

Relative risk

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SAFs

SMR

STEL

TAFs

TEM

TWA

WHO

U.S.

Short asbestos fibres

Standard error

Standardised mortality ratio

Short term exposure limit

Thin asbestos fibres

Transmission electron microscopy

Time weighted average

World Health Organization

United Kingdom

United States of America

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ECOMMENDATION FROM THE WORKING GROUP OF THE

ATIONAL

ESEARCH

ENTRE FOR THE

ORKING

NVIRONMENT

8-hour TWA: We recommend that the following

exposure levels leading to excess cancer risk

are

used:

Excess cancer incidence of lung

cancer or mesothelioma

1:1000

1:10 000

1:100 000

Risk levels (8h-TWA) based on a meta-analysis conducted by DECOS on Human

studies of mesothelioma and lung cancer combined – calculated based on exposure

to amphibole asbestos

0.01 fibres/mL

0.001 fibres/mL

0.0001 fibres/mL

The current working group calculated risk levels for lung cancer based on Danish incidence values and on

value for lung cancer set by DECOS. Notably, these were in line with DECOS’ own risk levels on lung

cancer.

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ECOMMENDATION EXECUTIVE SUMMARY

Derived Limit Values /Carcinogenic Risk Assessment

The current working group recommends that the following

risk estimates for asbestos-induced cancer

are used for health-based occupational exposure limits:

Table 1. Our recommendation on:

exposure levels leading to excess cancer risk

Excess cancer incidence of lung

cancer or mesothelioma

1:1000

1:10 000

1:100 000

Risk levels (8h-TWA) based on a meta-analysis conducted by DECOS on

Human studies of mesothelioma and lung cancer combined – calculated

based on exposure to amphibole asbestos

0.01 fibres/mL

0.001 fibres/mL

0.0001 fibres/mL

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ECOMMENDATION ON OCCUPATIONAL EXPOSURE

LIMITS FOR ASBESTOS

This recommendation is based on previous compilations performed by IARC (IARC, 2012),

DECOS (DECOS, 2010), German Federal Institute for Occupational Safety and Health (BAuA)

(BAuA, 2014), and Afsset (Afsset, 2009), as well as on evidence from the scientific literature based

on a literature search conducted in 2019 by the National Research Centre for the Working

Environment, Denmark.

1. Chemical agent identification and physico-chemical

properties

Name:

Asbestos

Synonyms:

Asbestos in the current report, and for the purpose of European Union Directive

2009/148/EC on the protection of workers from the risks related to exposure to asbestos at work

(EU, 2009), means the following fibrous silicates with listed Chemical Abstract Service (CAS) No :

(a) actinolite, CAS No 77536-66-4

(b) grunerite (amosite), CAS No 12172-73-5

(d) chrysotile, CAS No 12001-29-5

(e) crocidolite, CAS No 12001-28-4

(f) tremolite, CAS No 77536-68-6

Molecular formula:

Asbestos are silicate minerals containing such elements as Al, Ca, Mg and Fe.

The molecular formulas are presented in Table 3.

EC No.:

601-801-3

CAS No.:

Asbestos: 12172-73-5

; CAS numbers of each type are given in Table 2.

Molecular weight:

The molecular weights depend on the length of the individual fibres. The

molecular weights of the chemical formulas are listed in Table 2.

Description:

Asbestos consists of 6 different silicates, of which one, chrysotile has a serpentine

(leaf like) structure and the other 5 have an amphibole structure (a chain-like crystalline structure)

(Table 2, Figure 1). When considering one of these asbestos types, impurities of one or more of the

https://echa.europa.eu/substance-information/-/substanceinfo/100.121.453

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other types have to be taken into account. Impurities e.g. in chrysotile include a long range of

chemical elements as described by Platek et al., (1985).

In the EU countable asbestos fibres in relation to the OEL are defined as having a length >5 µm a

diameter of less than 3 µm and a L/D (aspect) ratio of ≥3.

In addition, there are asbestos fibres that

are less than 5 µm in length.

Figure 1. Overview of the asbestos types and their structures

Drawn based on

. The images stem from

. No scale-bars were available.

http://www.nzdl.org/gsdlmod?e=d-00000-00---off-0hdl--00-0----0-10-0---0---0direct-10---4-------0-1l--11-en-

50---20-about---00-0-1-00-0--4----0-0-11-10-0utfZz-8-00&cl=CL1.1&d=HASH011321ce4efc2579cf71e500.4&gt=2

http://www.jewellery.org.ua/stones-katalog-engl/mineral-serpentin.htm;

https://www.nationalasbestos.co.uk/types-of-asbestos/

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Figure 2. Proposed metabolism of amphiboles and serpentine asbestos in the mammalian body.

(A)

Structure and disassociation of amphibole fibre. The fibres are weakly connected by magnesium ions (orange

spheres) and are highly resistant to neutral or acid dissolution. (B) Structure and disintegration of chrysotile

fibre. The magnesium is dissolved at neutral pH and the silica matrix is broken up at acid pH. Modified

from D.M. Bernstein, J.A. Hoskins. The health effects of chrysotile: current perspective based upon recent

data, Regul.Toxicol Pharmacol. 45 (2006) 252-264.

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Table 2., Origin, mineral group and use of each of the six asbestos types constituting the designation of “asbestos” in the European

Union (EU); Supplemented with data on a seventh type (Libby amphibole)

Name

CAS number

Mineral group

Use

Chrysotile

12001-29-5 Institut für Serpentine (or curly in 90 – 95% of all asbestos used for the manufacture of

(white asbestos)

Arbeitsschutz

der nature)

products in the United States has been reported to be

Deutschen Gesetzlichen

chrysotile

A cement additive, a binding material in sealants, in

Unfallversicherung

many types of linoleum and floor tiles developed

(DGUV/IFA, 2018)

during the Twentieth Century, in congoleum products,

gasket materials for cars and for pumps, in asbestos

roofing materials used in several forms after World War II

and into the 1970s

Chrysotile made up 98% of the world asbestos

production in 1988 (DGUV/IFA, 2018).

Amosite

(brown 12172-73-5

Amphibole (straight, Amosite has a high absorption ability, and was

asbestos)

thin, needle-like fibres therefore commonly used in materials to reduce

Amosite is a trade

condensation or provide acoustic insulation against

name for brown

sound travel. Amosite’s tensile strength and heat

asbestos from South

resistance also made it a common additive for

African

mines.

structural steel

Amosite

acronym

for

‘asbestos mines of

South Africa’

http://www.asbestosnews.com/asbestos/types/

https://mesowatch.com/amosite-asbestos/#.XO5xMhYza70

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Crocidolite

asbestos)

Anthophyllite

(blue 12001-28-4

Amphibole

77536-67-5

Amphibole

Tremolite

Actinolite

77536-68-6

77536-66-4

Amphibole

Libby amphibole

The CAS number is

unknown

Amphibole

Crocidolite has a greater tensile strength than chrysotile

asbestos but is much less heat-resistant, fusing to black

glass at relatively low temperatures

Anthophyllite asbestos has a more brittle fibre than

other forms of the mineral and is formed by the

breakdown of talc, thus resulting in it being a common

contaminant in talc that is mined for commercial

purposes

Was a common additive in talcum powder when the

use of asbestos in commercial products was legal

Actinolite asbestos, the fifth member of the amphibole

class, is commonly found in a number of rock forms,

including iron ore. It has not been mined commercially

but nevertheless may be found as a contaminant in

asbestos products or in products derived from other

mined minerals.

Libby Amphibole Asbestos is a transitional fibre. It is

made of 3-5 chemically different fibres and the chemical

composition may change from one end of the

amphibole fibre to the other.

Tremolite is the form of asbestos that contaminated

the vermiculite mine in Libby Montana

https://www.britannica.com/science/crocidolite

http://www.asbestosnews.com/asbestos/types/

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Table 3. Chemical composition and data on physico-chemical properties of the 6 asbestos types

Serpentine

Amphibole

Type

Chrysotile

Anthophyllite

Crocidolite

Actinolite

Tremolite

Amosite

Chemical

(OH)

(Mg,Fe

)

(OH)

(Fe

2+,

Mg)

23+

(OH)

Si (Ca,Na)

(Fe,Mg,Al)

( Ca

(Mg,Fe)

(OH,F)

Si (Fe

,Mg,Al)

(OH)

formula

OH, F)

(Si, Al)

Si, Al)

Chemical composition in (%)

SiO

MgO

Iron

oxide

CaO,

35 - 44

36 - 44

0-9

52 - 64

25 - 35

1 - 10

49 - 57

3 - 15

20 - 40

Up to 63

18 - 33

2 - 17

50 - 63

18 - 33

2 - 17

45 - 56

4-7

31 - 46

0-2

12 - 15

0-1

1-5

prismatic crystal

and fibres

2-8

2-4

long, brittle fibres

1 - 10

1-4

1 - 10

1-4

1-2

1-3

prismatic crystal

and fibres

ash grey

rough

Physical

fine light

propertie

fibres

Colour

Texture

prismatic crystal and prismatic crystal and

fibres

green

rough

white, grey- white,

greenish

rough

white, grey, grey-white

greenish

soft to

rough

rough,

mostly silky

low

blue

soft to rough

Flexibilit

very high

good

low

good

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Fibre

diameter

(nm)

18 - 30

60 - 90

50 - 90

0 - 90

60 - 90

Melting

1500

point (°C)

pH-

9.5 – 10.3

Value

Electrical

charge in

aqueous

suspensi

1480

9.4

1180

9.1

1393

9.5

1320

9.5

1400

9.1

The Source of this table is: “Umweltbundesamt (Publ.): Analysis of the Asbestos Industry, written by the Battelle-lnstitut Frankfurt e.V.,

Report 4/78, Berlin 1978”

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2. EU harmonised classification and labelling

Information about the EU harmonised classification and labelling for asbestos (CAS number 12172-

73-5; EC Number 601-801-3; Index 650-013-00-6) is provided by the EU (EU, 2008), as summarised

in Table 4.

Table 4: Classification according to Regulation (EC) No 1272/2008 (EU, 2008) "List of harmonised

classification and labelling of hazardous substances" (found in Table 3.1. in the regulation)

International CAS No

Classification

Chemical

Identification

Hazard

Class Hazard

and

Category statement

Code(s)

Asbestos

12001-28-4

Carc. 1A STOT H350 H372 **

And individual types have the following RE 1

CAS numbers:

Actinolite, CAS No 77536-66-4

Grunerite (amosite), CAS No 12172-73-5

Anthophyllite, CAS No 77536-67-5

Chrysotile, CAS No 12001-29-5

Crocidolite, CAS No 12001-28-4

Tremolite,

CAS No 77536-68-6

Carcinogenic 1A: H 350: known to have carcinogenic potential for humans

STOT RE 1: H372 Causes damage to organs

3. Chemical agent and scope of legislation

Asbestos is according to the EU constituted by 6 different silicates as described above and in (EU,

2009); all of which are considered in the current document.

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4. Existing occupational exposure limits

At EU level, an OEL of 0.1 fibres/cm

has been adopted for asbestos. However, some EU Member States as well as countries outside the

EU have lower OELs as presented in in Table 5. There are to our knowledge no Biological Limit Values (BLVs) for asbestos available to

date.

Table 5. Existing OELs for asbestos

TWA (8 hrs)

Unit

Fibres/cm

0.1

µg/m

Not provided

directly in the

legislation

(EU,

2009).

However,

according to

the

Directive

87/217/EEC

(EU, 1987): “a

conversion

factor of two

fibres/mL to 0.1

mg/m

asbestos may be

used”.

Thus

STEL

(Short-term Remarks

exposure limit)

(15 min, in not stated

otherwise)

Fibres/cm

µg/m

Not

n/a

reported in

the

Commission

Directive

2009/148/EC

(EU, 2009)

Citation: “Fibre counting shall be

carried out wherever possible by

phase-contrast

microscope

(PCM) in accordance with the

method recommended in 1997 by

the World Health

Organization (WHO) (2) or any

other method giving equivalent

Results” from: (EU, 2009).

(2) Determination of airborne

fibre

concentrations.

recommended

method,

phase-contrast

optical microscopy (membrane

filter

method), WHO, Geneva 1997

Reference

Commission

Directive

2009/148/EC

Article 8

(EU, 2009)

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the

0.1

fibres/cm

corresponds

to 5 µg/m

Although we

note that this

depends

the length and

mass of each

fibre

(ISBN 92 4 154496 1).

EU states that: “For the purpose

of measuring asbestos in the air,

as referred to in paragraph 1,

only fibres with a length of more

than 5 micrometres, a breadth of

less than 3 micrometres and a

length/

breadth ratio greater than 3:1

shall be taken into consideration”

from (EU, 2009).

(see

comment

for EU

for TWA

above)

(see

comment

for EU

for TWA

above)

(DGUV/IFA, 2018)

Denmark

0.1

(see comment 0.2

for EU above)

Germany

TRGS 910

Substance-specific

acceptance and

tolerance

concentrations

Acceptance

concentration

Conc. (weight):

10000 F/m³ [0.01

Fibres/cm

]

Acceptance

concentration

0.8

Carcinogenic: Category 1

(DGUV/IFA, 2018)

Substances which cause cancer

and

make

considerable

contribution to the risk of cancer

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France

United

Kingdom

(UK)

The

Netherlands

Non-EU

United States 0.1

America(U.S.)

Switzerland

0.01

Japan

Japan JSOH

0.15

associated with risk

4:10,000

Tolerance

concentration

Conc. (weight):

100,000 F/m³

[0.1 Fibres/cm

]

Excursion factor: 8

also see TRGS 517, 519

0.01

(see comment

for EU above)

0.1

(see comment 0.6

(10 (see

for EU above) minutes)

comment

for EU

for TWA

above)

0.01

(see comment

for EU above)

(see comment

for EU above)

(see comment

for EU above)

(see comment

for EU above)

(see comment

for EU above)

(DGUV/IFA, 2018)

Only pertains to some of the fibre (DGUV/IFA, 2018)

types.

0.03 / 0.003

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5. Occurrence, use and occupational exposure

5.1. Occurrence and use

Asbestos is released to the environment through natural and man-made sources. Natural sources

include emissions from open mines. Man-made sources provide a much greater release volume

than natural sources. The largest single source in Denmark is from building materials and

materials e.g. locomotive parts, such as clutches, brake linings, and brake pads. These products

were mounted before 1987 when the use of asbestos in new products was banned in Denmark.

Concerning the ban on asbestos in Denmark in 1972, asbestos was prohibited in products for

thermal-, noise- and moisture isolation. In 1980 a ban was set on the use of asbestos and asbestos-

containing materials with the exception of asbestos-cement products such as roof tiling, frictional

surfaces, gasket materials,

“lejeforinger”

and

“kommutatorer”.

In 1986 the ban was strengthened.

After this date exceptions were only: ”asbestcementbølgeplader

“B5” og “B9” og håndgods til

tagdækning, bundne pakningsmaterialer, friktionsbelægninger, lejeforinger og kommutatorer”.

From 1993

to 2005 only few products such as “bundne

pakningsmaterialer, lejeforinger og enkelte

friktionsbelægninger”

have been exempted from the ban (Arbejdstilsynet, 2016).

In 1991 five of the six asbestos types were banned for all use in the EU and the remaining

type chrysotile was banned in 14 product categories. In 1999 Annex 1 of Directive 76/769/EEC

(European Economic Community) was updated (EU_Commission, 1999) to extend the ban to

chrysotile in asbestos cement products (mainly pipes and roofing), friction products (e.g. brake

clutch linings for heavy vehicles) and seals and gaskets as well as various specialist uses. By

January 1

2005 this EU commission directive 1999/77/EEC (EU_Commission, 1999) was brought

fully into force.

Airborne asbestos fibres are eliminated from the atmosphere through precipitation and dry

deposition. Important sources of individual exposure to asbestos are inhalation of contaminated

air at the workplace. Some environmental exposure cannot be excluded. Also contributions from

ingestion and dermal/mucosal surface exposure cannot be excluded.

Notably the various asbestos types are often contaminated with each other, and it has e.g.

been shown that even chrysotile samples from different mines that have similar size distribution

show differences in biological effects (Muhle and Pott, 2000).

The background ambient air levels for the Parisian conurbation is estimated to be 0.0003 fibres/mL

for fibres >5 µm and 0.002 for fibres <5 µm (Afsset, 2009).

5.2. Production and use information

Asbestos is mined from the earth several places around the world but in Denmark asbestos is not

produced or used anymore. Yet, Asbestos, although banned in 1987 for new products, is still

present in a range of materials installed before 1987.

5.3. Occupational exposure

Asbestos, although banned in 1987 for new products, is still present in some products in Denmark.

The current exposure levels from these sources are unknown. Examples of asbestos fibres of

different workplaces in Germany is given in Table 6.

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Table 6 Examples of asbestos fibre concentrations in the air (fibres/cm3) of different workplaces

in Germany.

Taken from IARC (IARC, 2012)

5.4. Routes of exposure and uptake

Occupational exposure to asbestos leading to uptake of fibres primarily occurs through inhalation.

Skin exposure (and mucosal surface exposure e.g. ocular exposure) occurs but is not expected to

result in systemic absorption through the skin due to the relatively large size of the asbestos fibres

(Bos and Meinardi, 2000). Oral absorption may occur e.g. if food is contaminated at the work site,

and possibly through the transport of fibres from the airways into the gastrointestinal tract. After

the oral route asbestos may be located in the organs (Carter and Taylor, 1980). When taken up the

asbestos fibres may distribute to various organs including the foetus of pregnant women (Haque et

al., 1998).

6. Monitoring exposure

6.1 Monitoring airborne asbestos in the workplace

Asbestos can be monitored in the air of the workplace by applying the following fully or partially

evaluated methods

In the EU Directive 2009/148EC (EU, 2009), the following is stated: “Fibre

counting shall be carried out

wherever possible by PCM in accordance with the method recommended in 1997 by the WHO or any other

method giving equivalent results. Determination of airborne fibre concentrations. A recommended method,

by phase-contrast optical microscopy (membrane filter method), WHO, Geneva 1997 (ISBN 92 4 154496 1)”

(EU, 2009).

In the EU asbestos fibres are defined as having a length >5 µm a diameter of less than 3 µm and a

length-to-diameter (L/D) ratio

of ≥3. However,

Afsset in France also investigated what they

designated

thin asbestos fibres

(L≥ 5 µm, d<0.2 µm and L/D≥3)

(Afsset, 2009). It was noted by Afsset

that if thin fibres were also to be measured then novel distinct methods would have to be used.

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6.2 Biomonitoring methods for asbestos in the workplace

Biomonitoring has to our knowledge not been applied for asbestos exposure.

7. Health effects

Asbestos fibres may cause various toxic effects. The carcinogenicity of individual asbestos types

has been demonstrated in humans and in a series of animal studies using different exposure

models (IARC, 2012). Genotoxic effects of asbestos were observed in numerous animal studies;

they were also detected in human cells in vitro (Afsset, 2009; IARC, 2012).

This chapter is based on literature search performed and documented by the NFA library. The

CAS numbers given by the EU: (a) actinolite, CAS No 77536-66-4; (b) grunerite (amosite), CAS No

12172-73-5; (c) anthophyllite, CAS No 77536-67-5; (d) chrysotile, CAS No 12001-29-5; (e) crocidolite,

CAS No 12001-28-4; and (f) tremolite, CAS No 77536-68-6 were checked in ChemIDplus and then

entered into the TOXLINE database combined with the search string: "inhalation exposure" OR

"lung deposition" OR instillation. This search was supplemented with searches by N. Hadrup in

the PubMed database using the word “asbestos” combined with relevant search terms on

absorption, distribution, metabolism, excretion, and toxicity. In addition to using search engines, a

number of relevant documents were identified by reviewing the reference list in other articles. The

result of the combined effort was the ~150 articles and reports included as references in the current

document.

7.1. Toxicokinetics (absorption, distribution, metabolism,

excretion)

Given that the likelihood of skin penetration of asbestos fibres is low (Davis et al., 1980a)(IARC,

2012), this chapter is focused on inhalation exposure, oral exposure, distribution to organs and

exposure of the foetus.

7.1.1. Human data

In general IARC (IARC, 2012) stated based in a National Toxicology Program (NTP) (NTP, 2005)

report that: “the

degree of penetration in the lungs is determined by the fibre diameter, with thin fibres

having the greatest potential for deep lung deposition”.

When investigating the human exposure it is difficult to pinpoint the exact pathway of exposure

although inhalation is often a likely contribution as the individuals either worked at or lived near

sites with high levels of asbestos. Also the potential of oral exposure occurs for the general

population as asbestos can enter potable water supplies. As reported by IARC (IARC, 2012): in the

U.S. the concentration of asbestos in the drinking water supplies is less than 1 fibres/mL. However

in some locations the concentration can be extremely high (10 000 – 300 000 fibres per mL,(Agency

for Toxic Substances and Disease Registry (ATSDR, 2001)).

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Exposure to asbestos as determined in biomonitoring of tissues from adults

Findings in lungs

Asbestos has been demonstrated in lungs of humans. In shipyard and construction workers with

mesothelioma all asbestos types, chrysotile, amosite, crocidolite, tremolite and what was

designated AAG (consisting of anthophyllite, actinolite and glaucophane) were detected

(Warnock, 1989).

In Quebec chrysotile miners and millers from

Asbestos Township,

fibre concentrations in lung

were compared to those in a local reference population. The individuals included 38 patients with

asbestosis without lung cancer, 25 with asbestosis and lung cancer, and 12 with mesothelioma:

these individuals were necropsied. The local reference population was: “men who had died of

either accidental death or acute myocardial infarction between 1990 and 1992. 23 were born before

1940 and 26 after 1940. Detected fibres were chrysotile, tremolite, crocidolite, talc, and

anthophyllite fibres. The pulmonary concentrations of each fibre type did not show any differences

between the three disease groups. Yet, there were some differences between the three disease

groups in regard to observed fibre dimensions (Dufresne et al., 1996).

Another study compared the deposition in lung of a) pulmonary asbestos; and b)

non-asbestos

fibres- in 1) rural Korean residents, and 2) urban Korean residents with no known asbestos

exposure. Chrysotile was the major fibre type in the lungs of both groups. The residents in the

rural area had lower asbestos and non-asbestos fibre concentrations as compared to the urban

residents (Lim et al., 2004). In a related study, the pulmonary asbestos and non-asbestos-fibres was

determined in 36 normal Korean individuals and in 38 individuals with lung cancer. Again,

chrysotile fibres were reported to be the major fibre type. No difference was found in the number

of fibres between the two groups. In contrast, the non-asbestos fibre content was different between

groups (Han et al., 2009)

Findings in organs other than lung

Auerbach

et al.

had the hypothesis that individuals with many asbestos bodies in their lungs

would also have asbestos bodies in other organs. Thirty-seven individuals, of which nineteen cases

had a diagnosis involving asbestos at death, were investigated. Of these, 18 had pleural plaques, 2

mesothelioma, and 5 lung cancer. Asbestos was found in lungs, but the number of other organs

with one or more asbestos bodies ranged from 32 to 62% of examined organs. The organs

examined were kidney, heart, liver, spleen, adrenals, pancreas, brain, prostate, thyroid (Auerbach

et al., 1980).

In another study, three men were investigated. Two of them had pulmonary asbestosis and one

had no known exposure to asbestos. Fibres were found in lung, pleura, bladder kidney and liver in

the cases with known exposure (Pollice et al., 1997).

Carter investigated tissues of persons orally exposed to amphibole fibres called

ferromagnesium silicate (Cummingtonite-Grunerite) from contaminated drinking water of Lake

Superior. The number of fibres ranged between 2x10

and 2x10

fibres/L. In exposed persons, fibres

were detected in lung, jejunum, liver. Both amphibole and chrysotile asbestos fibres were detected

(Carter and Taylor, 1980).

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Foetal exposure to asbestos

The tissues and placentas of autopsied stillborn infants were investigated for the presence of

asbestos fibres. Asbestos fibres were detected in 50% of digests of foetal tissue and 23% of the

digests of the placenta of 82 stillborn infants. There were various types present, 88% were

chrysotile, 10% were tremolite, and 2% were actinolite and anthophyllite. The organs that were

most frequently positive for fibres were: Lungs (50%), muscle (37%), placenta (23%), and liver

(23%). Nevertheless, the mean fibre counts were highest in the liver (58 736 fibres/g

), placenta (52

894 fibres/g), lungs (39 341 fibres/g), and in skeletal muscle (31 733 fibres/g). Concerning placentas

from live-born foetuses asbestos fibres were detected in 15% of these, but only in small numbers.

In placentas of the stillborn the fibre counts was 52 894 fibres/g whereas in live-born foetuses it

was only 19 fibres/g. The fibre presence in the stillborn foetuses was associated with the history of

previous abortions and with placental diseases (Haque et al., 1998). In a study by the same group

in 1996 similar results were obtained studying 40 stillborn infants and placental digests of 45 live-

born infants (Haque et al., 1996), and similar data were reported by the same group in 1992 (Haque

et al., 1992). Data in animals corroborated these findings - as described below (Haque et al., 2001;

Haque and Vrazel, 1998).

Summary

Asbestos has in workers been demonstrated in lungs but also in a range of other organs. In

addition, asbestos has been demonstrated in foetal tissues. In some workers all types of asbestos

can be found in the lungs - probably reflecting that the different types are impurities of each other.

7.1.2. Animal data

Inhalation exposure

Absorption and distribution

A range of animal inhalation studies were reviewed. There were data on absorption and

deposition for chrysotile, amosite and crocidolite. The data are presented graphically in Figure 3.

It was not specified if this was per wet or dry weight

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Figure 3. The distribution of asbestos in animals following inhalation

(illustration by N.

Hadrup)

Chrysotile

The accumulation of chrysotile after inhalation was observed in: the (alveolar) macrophages,

alveolar epithelial cells, pulmonary interstitium, lymphatics and in lymph nodes as well as in the

vascular compartment. The airway location was described to be in the bifurcations of the bronchi,

bronchioles and alveolar ducts. But fibres were also described to be located in the airspace and also

in so-called microcalcifications (Barry et al., 1983; Bernstein et al., 2004; BéruBé et al., 1996;

Boorman et al., 1984; Brody et al., 1981; Brody and Hill, 1982; Crapo et al., 1980; Davis et al., 1986a,

1980b; Hesterberg et al., 1998; Oghiso et al., 1984; Pinkerton et al., 1984; Platek et al., 1985; Roggli

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and Brody, 1984). Concerning the location in bifurcations of alveolar ducts, Brody et al described

this to be the site where the majority of fibres were located, and that the farther a bifurcation was

from its terminal bronchiole the fewer fibres were observed (Brody et al., 1981).

After inhalation exposure to amosite fibres, these were located in macrophages and multi-

nucleate foreign body giant cells (Davis et al., 1991); and observed in the interstitial space and also

found to be penetrating the visceral pleural wall and were observed on the parietal pleurae

(Bernstein et al., 2011).

After inhalation exposure to crocidolite, fibres were observed in alveolar macrophages, the

diaphragm, mediastinal lymph nodes, pulmonary interstitium (Bernstein et al., 2015; Oghiso et al.,

1984; Roggli et al., 1987). In one study crocidolite but not chrysotile deposition was found in lungs

(BéruBé et al., 1996). In Beagle dogs, inhalation of crocidolite resulted in a lung deposition of 17%

and a total body deposition of 63%. Excretion of radioactivity showed that the percent of initial

body burden fell from ~80% to a little more than 20% over the course of 3 days (Griffis et al., 1983).

This may reflect rapid clearance of the upper airways,

Metabolism and elimination

Chrysotile

In rats inhaling chrysotile, macrophages and epithelial cells were cleared of fibres during a

recovery period. In contrast, there was no clearance of fibres in the lung interstitium (Pinkerton et

al., 1984). In another study, in rats inhaling chrysotile, the elimination rate of short chrysotile fibres

was higher than observed for long fibres (Davis and Jones, 1988).

(Bernstein et al., 2006 exposed male rats to chrysotile by nose-only inhalation for 5 days/week, 6

h/day for 13 weeks. The fibre concentration was 1.3 mg/m

(having 76 fibres/cm

of fibres > 20

µm, or 3413 total fibres/cm

or 536 WHO fibres/cm

), and 3.6 mg/m

(having 207 fibres/cm3 for

fibres > 20 µm or 8941 total fibres/cm

or 1429 WHO fibres/cm

)The exposure period was followed

by a recovery periods of 0, 50 or 92 days. The content of long chrysotile fibres >20 µm in the lung

were found to decrease considerably during the recovery period, and it was inferred that the

longer fibres broke apart into particle and shorter fibres. Fibres were observed to become thicker

during the recovery period at the medium dose (Bernstein et al., 2006).

Rats were exposed to chrysotile fibres at 4.3 mg/m

. The duration was 6h/day for 5 days. After the

exposure there were recovery periods of 1, 2, 7, 14 days, 1, 3, 6 and 12 months. The clearance half-

time of the fibres longer than 20 µm was 1.3 days. No fibres longer than 20 µm were observed 3

months after exposure (Bernstein et al., 2004).

Rats inhaled chrysotile at a mass concentration of 15 mg/m

for 1 h. Animals were euthanised

following recovery periods of 0, 24, 192, 336, and 744 h (1 month). There was a progressive

decrease in fibre diameter ranging from 0.17 at 0 h to 0.1 µm at 744 h. (Roggli and Brody, 1984).

Rats were exposed to Calidria chrysotile or tremolite by inhalation. Mass concentrations were for

chrysotile 200 fibres having a length of at least > 20 µm/cm

(1.7 mg/m

); and for tremolite 100

fibres having a length of at least > 20 µm/cm

(11.5 mg/m

). It was stated that the exposure

technique was optimised to maximise the number of long respirable fibres. The exposure time was

6 h/day for 5 days. Animals were killed at 0, 1, 2, 7 days, 2 weeks, 1 month, 3 months, 6 and 12

months after exposure. After a recovery period of 12 months 99.2% of remaining chrysotile in the

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lungs was shorter than 5 µm. In contrast, tremolite exposure showed persistence with what was

described as essentially an infinite half-time (Bernstein et al., 2005).

Rats inhaled a) brake-dust of brake-drums made from chrysotile, b) a mixture of chrysotile and the

brake-dust, or c) crocidolite. Exposure time was 6h/day for 5 days. The concentrations were a) 189

fibres ≥ 20 µm/cm

, b) 3.6 fibres ≥ 20 µm/cm

, c) 93 fibres ≥ 20 µm/cm

(the total number of fibres

were 6953, 389, and 2013/cm

in the three groups, and the mass concentrations 3.5, 1.5, and 6.3

mg/m

). Chrysotile fibres were observed to be somewhat bio-soluble in that short (<8 µm) fibres

decreased rapidly for as long as 30 days after exposure, and continued to decrease for as 180 days

of exposure. Longer fibres decreased to around 50% during the first 30 days, but then there was

almost no further clearance during the period ranging from 30 to 180 days. In comparison,

crocidolite fibres persisted for the life-time of the rats (Bernstein et al., 2015). Rats inhaled

chrysotile asbestos at 10 mg/m

for 3-5 hour periods over 3 consecutive days (~12 h). Recovery

periods were in the range of 1 to 180 days. Deposition was investigated, whereas short fibres were

rapidly cleared, a large number of the longest fibres, defined as longer than 8 µm, were observed

in the lungs for up to 6 months (Coin et al., 1996).

Amosite

Rats were exposed by nose-only inhalation to Libby amphibole and amosite 6h/day 5 days/week

for a total of 10 days (mass concentration: Libby amphibole: 0.5, 3.5, or 25.0 mg/m

and amosite

asbestos: 3.5 mg/m

). Or alternatively exposure to Libby amphibole: 1.0, 3.3, or 10.0 mg/m

amosite at 3.3 mg/m

for 6 h/day, 5 days/week for 13 weeks. Endpoint evaluation was done at 1

day, 1, 3, and 18 months post exposure. Lung fibre burdens investigated at 13 weeks of exposure

declined over the 18 month post exposure period. Libby amphibole fibres had a mean length of 3.7

µm, with 1% being longer than 20 µm (Gavett et al., 2016).

Rats were exposed by inhalation to amosite at 6.4 mg/m

6 h/day for 5 days. The length the number

of fibres longer than 20 µm decreased only slightly over a 1 year recovery period, from 2.8 million

fibres per lung at the end of exposure to 1.4 million at 1 year of recovery (Bernstein et al., 2011).

Rats inhaled 1000 amosite fibres (longer than 5 µm)/mL, 7 h/day, 5 days/week for 12 months.

Assessment of elemental composition of fibres recovered from the lungs showed that these

contained 61% Fe, 32% Si, 1.2 % Mg and 1.3 % Ca at the end of recovery (essentially the same

composition as untreated fibres). After an additional 12 months of recovery, 44% of the fibres were

still present for amosite (Cullen et al., 2000).

Crocidolite

Rats were exposed by inhalation to chrysotile or crocidolite asbestos. The mass concentration was 8

mg/m

and the time period was for 5 or 20 days. The latter period was followed by a 20 day post-

exposure period. Inhalation of crocidolite resulted in a higher fibre lung retention as compared to

the inhalation of chrysotile fibres (BéruBé et al., 1996). Rats inhaled crocidolite at mass

concentrations of 3.5 mg/m

or 4.5 mg/m

. The duration was 1 h and recovery periods were 0 h, 2

days, 8 days, 4 weeks, 2 months, or 3 months. A progressive increase in mean fibre length with the

time post exposure was observed. No changes were observed in the diameter of crocidolite fibres

in the lung. Thus the longitudinal splitting described previously for serpentine fibres was not

observed for crocidolite (Roggli et al., 1987). Rats were exposed by nose-only inhalation to

crocidolite. The mass concentration of crocidolite was 10 mg/m

. The exposure period was 6 h/day

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for 5 days. Lung fibre burden was evaluated by use of electron microscopy during a subsequent 1-

year period. Only 17% of long crocidolite fibres longer than 20 µm were eliminated. The mean

diameter of the crocidolite fibres remained unchanged, whereas the mean length had increased.

The latter was likely due to the elimination of shorter fibres. No morphological or chemical

changes were observed in crocidolite fibres (Hesterberg et al., 1996).

The number of crocidolite fibres in rats of lungs exposed to 8 mg/m

crocidolite 6 h/day, 5 days a

week for a total of 20 days, did not decrease substantially over an additional 20-day recovery

period (BéruBé et al., 1996).

Tremolite

Rats were exposed to tremolite by inhalation of 11.5 mg/m

(100 fibres having a length of at least >

20 µm/cm

). The exposure duration was 6 h/day for 5 days. It was stated that the exposure

technique was optimised to maximise the number of long respirable fibres. Recovery periods were

0, 1, 2, 7 days, 2 weeks, 1 month, 3 months, 6 and 12 months after exposure. Tremolite exposure

showed persistence with what was described as essentially an infinite half-time (Bernstein et al.,

2005).

Oral exposure

A baboon was administered cumulative doses of 800 mg each of chrysotile and crocidolite asbestos

by gavage. Penetration of the gastrointestinal tract and migration to the stomach, heart, spleen,

pancreas, and blood was observed (Kaczenski and Hallenbeck, 1984). In one baboon administered

chrysotile by gavage, fibres were observed in the urine (Hallenbeck and Patel-Mandlik, 1979).

Rats were administered asbestos via the drinking water at 1.5 or 3 g/L. After 6 and 9 months of

chrysotile exposure, mesothelial proliferation and asbestos bodies were observed in the lungs and

pleura. At 9 months, asbestos was observed in the spleen with dose-dependency. Mesothelial

proliferation was observed in the high dose group at 12 months. The authors of that study

concluded that the ingested asbestos traveled from the gastrointestinal system to the lungs, and

that this likely occurs via a “lympho-hematological” route and that this lead to mesothelial

proliferation and ultimately carcinogenicity (Hasanoglu et al., 2008). Cunningham

et al.

found that

rats ingesting chrysotile - 1% in the diet for 6 weeks - had elevated levels of fibres in all

investigated tissues. The highest levels were observed in the omentum, followed by: brain, lung

liver, blood, and kidney (Cunningham et al., 1977).

A gavage study gave data concerning the trans-placental transfer of asbestos in pregnant

mice. Pregnant mice were administered two doses each of 50 µg chrysotile. After mating, the mice

received two additional doses. The lungs and liver of pups were found to contain 780 chrysotile

fibres/g lung and 214 /g liver. Weight gain and mortality was not different from that of pups in a

control group (Haque et al., 2001).

Summary

Following inhalation exposure of animals, asbestos was observed in a range of pulmonary

structures and cell types (Figure 3) as well as in the lymphatic and vascular compartment. In the

lungs of rats, chrysotile has been described to break into smaller fibres, be somewhat bio-soluble

and have a considerably lower persistence in comparison to tremolite and crocidolite fibres.

Amosite was also reported to have a low clearance. The difference in elimination of the serpentine

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chrysotile and the amphibole asbestos types likely reflects that they break up in different ways

inside the mammalian body – as illustrated in Figure 2.

Following oral exposure, asbestos was found in a range of organs in baboons and rats

including distribution to the rat lung. Trans-placental transfer of asbestos has been demonstrated

in rats.

7.1.3. In vitro data

The data on the inhalation exposure of animals to different asbestos types are sufficient to provide

a picture on the absorption, distribution, metabolism and excretion (ADME) properties of asbestos.

Therefore, the application of in vitro models is not needed.

7.1.4. Toxicokinetic modelling

The data on the inhalation exposure of animals to different asbestos types are sufficient to provide

a picture on the ADME properties of asbestos. Therefore, the application of toxicokinetic

modelling is not deemed relevant.

7.1.5. Biological monitoring

There is no evidence in the literature that biological monitoring e.g. through urine or

blood metabolites is routinely applied; the serum level of mesothelin-related proteins has

been proposed as a biological marker of the development of mesothelioma (Robinson et

al.,

2003).

7.2. Acute toxicity

7.2.1. Human data

In 2009 Afsset reported that no evidence of acute toxicity of asbestos was found (Afsset, 2009). We

also found no relevant data in our literature search.

7.2.2. Animal data

We found some relevant data concerning inhalation exposure of short acute duration. These are

however mostly focussed on the investigation of cell proliferation, e.g.: (Barry et al., 1983; Chang et

al., 1988). In the current document we, in the light of the high number of inhalation studies with

asbestos, only shortly describe the most relevant intratracheal instillation studies in the remainder

of this section. The reason for this is that inhalation studies are in general of higher priority in

hazard assessment than intratracheal instillation studies.

Rats were administered amosite at 0.65 mg/rat, or Libby amphibole at 0.65 or 6.5 mg/rat.

Recovery periods were 1 day or 3 months. Amosite at 0.65 mg resulted in higher levels pulmonary

injury, inflammation, and fibrotic events as compared to the equal dose of Libby amphibole.

Amosite, 0.65 mg/rat, and Libby amphibole, 6.5 mg/rat, resulted in increased cellular permeability

and injury, inflammatory enzymes, and iron binding proteins in both bronchoalveolar-lavage

(BAL) fluid and lung tissue and lower Messenger-RNA (mRNA) levels of some growth factors.

Pathological findings were: thickening of interstitial areas surrounding the alveolar ducts and

terminal bronchioles (Padilla-Carlin et al., 2011). Rats were administered Libby amphibole or

amosite by intratracheal instillation of 0.15, 0.5, 1.5, or 5 mg/rat. These doses were administered

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either as single or multiple doses over 13 weeks. Recovery periods lasted up to 20 months. Libby

amphibole resulted in more pronounced neutrophilic inflammation and cellular toxicity as

compared to amosite; whereas histopathological changes were similar for the two groups.

Mesothelioma and lung carcinomas were observed only in single animals (not statistically

significantly) both after exposure to low and high doses of these two asbestos types (Cyphert et al.,

2015). Rats were administered amosite by intratracheal instillation at doses ranging between 0.05

and 1.0 mg/rat. Recovery periods were 1, 3, and 7 days. Amosite exposure resulted in increased

total protein in BAL fluid at the highest dose for all time points and on day 1 at all doses. These

effects were normalised at 7 days of recovery (Ishihara et al., 1999). A study in mice using

aspiration exposure to 100 µg crocidolite suggested that a change in the redox status of the lung

was associated with acute asbestos induced lung injury (Leonard et al., 2002).

Summary:

In summary, some acute effects such as increased proliferation of cells in the

airways, increased cytotoxicity of airway cells and acute lung injury have been reported.

7.2.3. In vitro data

Relevant data on genotoxicity are presented in the section of genotoxicity.

7.3. Specific Target Organ Toxicity/Repeated Exposure

7.3.1. Human data

In addition to cancer, inhalation of asbestos types has also been linked to other pulmonary and

pleural conditions. The most important adverse effect besides of cancer is asbestosis, but other

conditions described by the French Agency for Food, Environmental and Occupational Health &

Safety (ANSES) are pleurisy and diffuse pleural fibrosis (Afsset, 2009).

Asbestosis

Asbestosis is a disease specifically occurring after the exposure to asbestos, hence the name. The

following section is based on a review article by (Lazarus and Philip, 2011), and an original article

by (Roggli et al., 2016). Inhaled asbestos fibres can lead to pulmonary fibrosis, which has a latency

of 20-30 years and is often mild, but can progress to diffuse pulmonary fibrosis. Pulmonary fibrosis

often begins at the subpleural level at the respiratory bronchioles. As fibrosis progresses, it

involves the alveolar ducts, alveolar septa, and terminal bronchioles. Rarely, in advanced cases, so-

called honeycombing with cysts and fibrotic walls may occur; and areas of desquamative

interstitial pneumonia may also be present. Asbestos fibres are at this stage only detectable with

iron stain. The presence of asbestos bodies in the alveoli or interstitium, with pulmonary fibrosis

on histology, supports a diagnosis of asbestosis. Frequently, diffuse visceral pleural fibrosis is

associated with pulmonary fibrosis. Another change that might be evident is parietal pleural

plaques that may or may not be calcified (Lazarus and Philip, 2011; Roggli et al., 2016).

Concerning the amount of asbestos needed to incite asbestosis, Omland

et al.

published a review

article in which they wrote that there is an unofficial lower limit for the recognition of asbestosis

and that this is at 25 fibre years (1 fibre year = number of years exposed at 1 fibre/cm

) and that this

is similar to the cumulated exposure estimate that increases the risk of lung cancer by a factor 2

(Omland et al., 2018). Concerning studies in which dose response relations were considered,

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Huang (Huang, 1990) found an expected asbestosis prevalence of 3% at a cumulated exposure of

43 fibre years and of 1% at 22 fibre years. Hein reported a hazard ration of about 2 at an exposure

of 50 fibre years (Hein et al., 2007), and Berrry

et al.

(Berry et al., 1979) concluded that a 1%

prevalence was associated with 55 fibre years in cumulated exposure. Stayner

et al.

found no

threshold value for asbestos exposure and asbestosis (Stayner et al., 1997). Finkelstein

et al.

described sigmoid dose response curve (with an X-axis unit of “fibres/mL x years

”) in which the

1% prevalence for asbestosis was related to 10 fibre years (Finkelstein, 1982).

Discussion on whether asbestosis could be the critical effect used for hazard assessment

The question is whether these asbestos exposure–response relations warrant that asbestosis

constitutes the critical effect for setting a health based OEL. If we for example consider the 10 fibre-

years giving a prevalence of 1%, as reported by Finkelstein, then a 1x10

-5

risk would correspond to

0.00025 fibres/cm

(10 fibres/cm

/ 40 years = 0.25 fibres/cm

for a risk of 1x10

-2

). The 1x10

-5

risk

levels calculated by DECOS (DECOS, 2010), and discussed below, are 0.0005 fibres/cm

for

chrysotile and 0.0001 fibres/cm

for amphibole types. Thus the risk of asbestosis could be

suggested to be in the range of lung cancer/mesothelioma - used by DECOS - if a linear

extrapolation is used. There is some indication of a threshold for asbestosis as described above, but

there are also references that describe that a threshold could not be determined (Stayner et al.,

1997). At the same time the current working group is of the opinion that the carcinogenic effect of

asbestos should be considered not to have a threshold mechanism and therefore linear

extrapolation is warranted for this effect. Nevertheless, we cannot totally exclude that asbestosis

occurs at exposure levels similar to those inducing carcinogenicity. On the other hand there is not

much evidence to support that asbestosis occurs at lower exposures than those inducing

carcinogenicity. Thus in the current document we use carcinogenicity as the critical effect but note

that asbestosis has been described at similar levels of exposure.

Summary

Asbestosis is a disease of pulmonary fibrosis occurring after exposure to asbestos. We do not

assess asbestosis to represent the critical effect. This is based on the likelihood of a threshold

mechanism of action – as compared to an absence of threshold in asbestos-induced cancer.

7.3.2. Animal data

7.3.2.1. Inhalation

Inhalation data have been extensively reviewed by the current working group. In summary most

inhalation studies have been conducted at a mass concentration of asbestos fibres of about 10

mg/m

, with some exceptions in the range of 1 to 10 mg/m

. When considering

non-cancer

endpoints, e.g. fibrosis, pathological lesions or lung function endpoints - these provide lowest

observed adverse effect concentrations (LOAECs) and no observed adverse effect concentrations

(NOAECs) in the range of 1 to 10 mg/m

and these dose descriptors are summarised in Figure 4.

Also, the findings in the chronic and subchronic investigations are summarised in the following

text sections. To limit the extent of this document the findings of subacute and shorter duration

studies are only presented in the graphs in Figure 4. As inhalation data are considered the most

relevant data for hazard assessment, no data following intratracheal instillation were included.

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C h r y s o tile N O A E C a n d L O A E C v a lu e s

100

S m it h 1 9 8 7 , R a t

B ro d y 1 9 8 9 , R a t B e ru b e 1 9 9 6 , R a t

C o in 1 9 9 6 , R a t D o n a ld s o n 1 9 8 8 , R a t

A m o s it e N O A E C a n d L O A E C v a lu e s

M a s s c o n c e n t r a tio n ( m g /m )

M a s s c o n c e n t r a t io n ( m g / m )

B ro d y 1 9 8 2 , R a t C h o e , 1 9 9 7 , R a t

C h a n g , 1 9 8 8 , R a t B a rry 1 9 8 3 , R a t

D ix o n 1 9 9 4 , M o u s e

B o o rm a n 1 9 8 4 , M o u s e

D a v is 1 9 8 9 , R a t

C ra p o 1 9 8 0 , R a t

H e s te rb e rg 1 9 9 8 , R a t

D a v is 1 9 8 6 , R a t

B e r n s t e in 2 0 0 6 , R a t

C ra p o 1 9 8 0 , R a t

B e r n s t e in 2 0 0 5 , R a t

B e r n s t e in 2 0 0 6 , R a t

B e r n s t e in 2 0 1 1 , R a t

P la t e k 1 9 8 5 , R a t

P la t e k 1 9 8 5 , M o n k e y

G a v e tt 2 0 1 6 , R a t

0 .1

1000

2000

3000

4000

500

1000

1500

2000

T im e (h )

C h ry s o tile N O A E C

C h ry s o tile L O A E C

T im e (h )

A m o s ite < 5 µ m N O A E C

A m o s ite > 5 µ m L O A E C

A m o s ite L O A E C

C r o c id o lit e N O A E C a n d L O A E C v a lu e s

M a s s c o n c e n t r a tio n ( m g /m )

T r e m o lit e N O A E C a n d L O A E C v a lu e s

M a s s c o n c e n t r a tio n ( m g /m )

100

Choe, 1997, Rat

B e r n s t e in 2 0 1 5

B e ru b e 1 9 9 6 , R a t

B e r n s t e in 2 0 0 5 , R a t

100

150

T im e (h )

C r o c id o lite L O A E C

T im e (h )

T re m o lite L O A E C

Figure 4. Overview of

non-cancer

endpoint resulting in NOAEC and LOAEC values in animal

subchronic and chronic inhalation studies.

A: Chrysotile, B: Amosite, C: Crocidolite, and D:

Tremolite.

Chrysotile Subchronic studies

Rats were exposed by inhalation to chrysotile at a mass concentration of 9 mg/m

. Exposure to

chrysotile for 3 months (420 h) resulted in increased numbers and volume of type II cells in the

epithelium. Also an increase in number and cell volume was observed in the interstitial cell

population. These latter increases were almost accounted for by changes in interstitial

macrophages. Microcalcifications were observed in interstitial macrophages (LOAEC: 9 mg/m

)

(Barry et al., 1983). Rats were exposed to chrysotile by inhalation. The mass concentration was 10.7

mg/m

. The duration was 6h/day, 5 days/week for 91 days. The animals were killed at 2 to 16

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months after cessation of exposure. Exposure to chrysotile was associated with thickened alveolar

duct bifurcations associated with aggregates of macrophages. Exposure to chrysotile resulted in

microcalcifications and slight pulmonary fibrosis (no NOAEC is set by the current working group

as no statistics was applied to the effects) (Oghiso et al., 1984).

Rats were exposed to chrysotile by nose-only inhalation for 5 days/week, 6 h/day for 13 weeks

(390 h). The fibre concentration was 76 fibres (having a length of more than 20 µm)/cm

(equal to

3413 total fibres/cm

or 536 WHO fibres/cm

) (1.3 mg/m

) or 207 (having a length of more than 20

µm)/cm

(equal to 8941 total fibres/cm

or 1429 WHO fibres/cm

) (3.6 mg/m

). The exposure period

was followed by a recovery periods of 0, 50 or 92 days. Inhalation of chrysotile resulted in

increased lung weights at both mass concentrations, however this difference was normalised at 92

days of recovery. Concerning the number of neutrophils, lactatdehydrogenase (LDH) and total

protein in BAL, these were increased at the end of the exposure to high dose. And for LDH and

total protein also at both dose level at 92 days of recovery. Slight fibrosis in was reported in the

lung at the highest dose, but not at the lowest (no statistics applied) (NOAEC

neutrophils/fibrosis

: 1.3

mg/m

) (Bernstein et al., 2006).

Chrysotile chronic studies

Monkeys and rats inhaled short chrysotile fibres at 1 mg/m

, 7 hr/day, 5 days/week for 18 months

(2730 h). In monkeys, lung biopsies were recovered 10 months after end of exposure. No fibrosis

was observed (NOAEC monkey 1 mg/m

). In rats exposure to the fibres did not result in fibrosis.

Also no other lesions were detected by gross and histopathologic examination (NOAEC rat 1

mg/m

) (Platek et al., 1985). Rats were exposed by inhalation to chrysotile fibres (National Institute

of Environmental Health Sciences (NIEHS) short-range and NIEHS intermediate-range fibres). The

mass concentration was for short fibres 3.1 mg/m

(192 x 10

fibres/m

) and for intermediate fibres

9.4 mg/m

(13 x 10

fibres/m

). The duration was 1 h, 7 h, 5 days, 3 months and 12 months (7 h /day,

5 days/week) (up to 1820 h). Increases in the volume of the alveolar epithelium, the interstitium

and in alveolar macrophages were observed at 3 months of exposure to either type of chrysotile

fibre. More pronounced lung pathology in the alveolar epithelium and the interstitium was

observed after 12 months of exposure to intermediate-range chrysotile fibres. Decreases in total

lung capacity and in vital capacity were observed at 12 months of exposure by both particle

lengths, although more pronounced after exposure to the intermediate-range fibres (LOAEC short

3.1 mg/m

, LOAEC intermediate 9.4 mg/m

) (Crapo et al., 1980).

Amosite subchronic studies

Rats were exposed by nose-only inhalation to amosite (or Libby amphibole) 6h/day 5 days/week

for a total of 10 days (mass concentration: Libby amphibole: 0.5, 3.5, or 25.0 mg/m

and amosite

asbestos: 3.5 mg/m

). Or alternatively exposure to Libby amphibole: 1.0, 3.3, or 10.0 mg/m

amosite at 3.3 mg/m

for 6 h/day, 5 days/week for 13 weeks. Investigations were done at 1 day, 1, 3,

and 18 months post exposure. Lung fibre burdens investigated at 13 weeks of exposure declined

over the 18 month post exposure period. Libby amphibole fibres had a mean length of 3.7 µm with

1% being longer than 20 µm. Increased lung inflammation, fibrosis, bronchiolar epithelial cell

proliferation and hyperplasia, as well as increased inflammatory cytokine gene expression were

observed with 25.0 mg/m

Libby amphibole exposure for 10 days. Markers of acute lung injury and

inflammation were increased by 3.5 mg/m

Libby amphibole as compared to amosite exposure.

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BAL markers of inflammation as well as lung associated cytokines were increased by both fibres

with exposure periods ranging from 1 day to 3 months. Concerning pathological changes, alveolar

inflammation was observed at all doses with both asbestos types, while interstitial fibrosis was

only found at 25 mg/m

Libby amphibole. Alveolar epithelial hyperplasia and bronchiolar/alveolar

adenoma or carcinoma were observed to show

positive trends

in Libby amphibole exposed animals

(Amosite LOAEC

neutrophils

: 3.3 mg/m

) (Gavett et al., 2016).

Crocidolite subchronic studies

Rats were exposed to crocidolite (amphibole) or chrysotile (serpentine) by inhalation. The mass

concentration was for crocidolite 11.2 mg/m

and for chrysotile 10.7 mg/m

. The duration was

6h/day, 5 days/week for 91 days (estimated to be 390 h). The animals were killed at 2 to 16 months

after cessation of exposure. Both materials were after inhalation associated with thickened alveolar

duct bifurcations associated with aggregates of macrophages. Exposure to crocidolite was also

associated with subpleural collections of alveolar macrophages and lymphocytes. Exposure to

chrysotile resulted in microcalcifications. Slight pulmonary fibrosis was observed following

exposure to either of the materials (no NOAEC set because no statistics was applied to the effects)

(Oghiso et al., 1984).

Crocidolite chronic studies

Rats were exposed to crocidolite asbestos. The mass concentration was 10 mg/m

6 h/day for 5

days/week and the period of exposure was in the range of 1 day to 12 months (up to 1560 h).

Exposure to crocidolite was associated with an increase in type II cells in the lung at day 1 and the

number of interstitial and alveolar macrophages were increased after 3 months. Forty-nine percent

of the alveolar macrophages contained particles after 1 day and 92 percent contained particles after

12 months. Also the number of particles in each cell was increased with increased time period. The

interstitium of airway bifurcations were the initial sites where cell damage and collagen deposition

was observed. The finding of weak fibrosis was by the current working group considered too

weak to set a NOAEC/LOAEC (Johnson, 1987).

Summary

In the majority of the assessed studies, the tested aerosol concentrations were in the range of 1 to

10 mg/m

, with most studies testing at the highest level. The NOAEC and LOAEC values are all

located at these levels, although - for chrysotile - there seems to be a level at 1 mg/m

where there

is generally no toxicological effect of the asbestos exposure. Concerning the nature of the effects,

these were of pathological findings including for example fibrosis and hyperplasia; but also of

inflammatory effects were observed - including altered bronchoalveolar lavage cellularity.

7.3.2.2. Oral exposure

We only identified one relevant study: Rats were administered chrysotile or a mixture of

chrysotile/crocidolite (75%/25%) in a palm oil vehicle. The duration was 24 months and the doses

were 10, 60 and 360 mg/day. Both normal diet and a palm oil control groups were included. A

recovery period of 6 months was included. No toxic effects (including no carcinogenic) were

observed (Truhaut and Chouroulinkov, 1989).

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7.3.2.3. Dermal exposure

We identified 26 references. Of these, there was one relevant study on the carcinogenicity of

asbestos on the skin of mice (Roe et al., 1966). This study is described in the section of

carcinogenicity.

7.3.3. In vitro data

No relevant data upon repeated exposures were identified.

7.4. Irritancy and corrosivity

7.4.1. Human data

Asbestos fibres seem not to have irritating or corrosive effects on the skin. No relevant data were identified

on asbestos and corrosion or on asbestos and irritation.

7.4.2. Animal data

7.4.2.1. Skin

No relevant data were identified.

7.4.3. In vitro data

No relevant data were identified.

7.5. Sensitisation

The potential is low as demonstrated by a lack of literature on the subject.

7.5.1. Human data

No specific data on sensitisation were identified.

7.5.2. Animal data

No specific data on sensitisation were identified.

7.5.3. In vitro data

No specific data on sensitisation were identified.

7.6. Genotoxicity

A key question when making suggestions for health-based OELs is: whether or not a compound’s

genotoxic effect occurs by a mechanism of action that involves a threshold? In the end of each

section in 7.6 we include a paragraph that summarises the evidence for and against a threshold

effect.

When determining levels of exposure that are safe to humans it is important to know

whether the carcinogenic mechanism of action involves a threshold effect. In the case of absence of

thresholds as is for example the case for mutagenic substances that form DNA-adducts) (such as

vinyl chloride), a linear extrapolation (the Linear no-threshold model (LNT)) model is applied to

calculate levels that are relatively safe for humans (Bolt et al., 2004). In contrast if a threshold is

present as has been suggested for 2,3,7,8-Tetrachlorodibenzo-p-dioxin, then a no-observed-

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adverse-effect level (NOAEL) can be adjusted with assessment factors to set an OEL (Bolt et al.,

2004).

In the current document the current working group have reviewed the evidence for and against

a threshold effect of asbestos-induced carcinogenicity. And discuss the placement into the concept

of non-threshold effect with numerical risk assessment or of a threshold as defined by (ECHA,

2016) (The concept is presented in Figure 5). To do this, we retrieved the literature on asbestos and

mutagenicity/genotoxicity and assessed whether the observed effects could be classified as

mutagenic (DNA reactive) or genotoxic - according to the categorisation presented in Figure 5. The

evidence was then collectively evaluated to determine whether asbestos fibres should be hazard

assessed using a linear non-threshold approach or if they can be placed into the practical/apparent

or the perfect/statistical categories to justify the use of assessment factors for threshold effects in

the hazard evaluation of asbestos.

Figure 5. The concept of a non-threshold or threshold mechanisms as described in the REACH

R.7a guidance.

The numerical risk assessment designation used by ECHA corresponds to a non-

threshold assessment, whereas the NOAEL designation corresponds to the presence of a threshold

as low as reasonable achievable (ALARA). The diagram is made by Niels Hadrup based on text in

(ECHA, 2016).

7.6.1. Human data

There was no relevant data

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7.6.2. Animal data

Gene mutations in mammals (transgenic assays)

Amosite

Big blue rats (containing a

lacZ

reporter gene) were exposed to amosite by intratracheal

instillation of with either single doses of 1 or 2 mg or with 4 doses per week of each of 2 mg/rat.

Recovery periods were 4 and 16 weeks, After 16 weeks of recovery, the mutation frequency was

increased in lung at both the single dose of 2 mg and at the four times 2 mg dosage. There was no

effect after the shorter 4 week of recovery period. In wild type rats, amosite in the same dosage

regimen induced DNA strand breaks in macrophages and type II cells as measured in the comet

assay. Micronuclei were increased in alveolar macrophages at 16 weeks but not after the shorter 4

week recovery period, there were no effects on this endpoint in lung epithelial cells (Topinka et al.,

2004).

Crocidolite

Mice transgenic for the

lacI

reporter gene were exposed to crocidolite by nose-only

inhalation to 5.75 mg/m

for 6 hr/day for 5 days. The experiment was terminated 1, 4, and 12 weeks

after the beginning of exposure (Recover periods ~0, 3 and 11 weeks). After 4 weeks, the mutant

frequency was increased by crocidolite. However this effect was not seen at 1 or 12 weeks.

The

mutation spectrum of control lung DNA and exposed lung DNA was similar,

and the authors of that

study suggested

the possible involvement of a DNA repair decrease in crocidolite-treated animals

(Rihn et

al., 2000). The current working group notes that if the mutation frequency is only increased by

15%, then only 15/115=13% of the mutations can be expected to be caused by asbestos exposure,

and thus, the mutation spectrum will appear similar to the background spectrum. Crocidolite was

administered to mice by pharyngeal aspiration and one year later K-ras mutations were evaluated.

Crocidolite at 120 µg, in contrast to single-walled carbon nanotubes and carbon fibres, did not

increase the incidence of K-ras oncogene mutations in the lung. None of the 3 fibre types increased

the lung tumour incidence (Shvedova et al., 2014).

Rats were dosed with crocidolite by intraperitoneal injection of 2 mg. DNA fingerprint

analysis of induced tumours showed a mutation frequency of 14.8%; in comparison

benzo[a]pyrene and nickel powder induced frequencies of 18.2 and 40.9%, respectively. A negative

control of NaCl injection was included in the study. In this control group only a few peritoneal

tumours were detected and these tumours exhibited no mutations in the fingerprint assay (Kociok

et al., 1999).

LacI

transgenic rats were exposed to crocidolite by intraperitoneal injection. The

mutation frequency was investigated in omenta – representing a relevant target tissue for

mesothelioma carcinogenesis. The doses were 2 and 5 mg, and the recovery periods were 4, 12 or

24 weeks. Crocidolite at 5 mg increased the mutation frequency at 12 and 24 weeks of recovery.

There was a difference in mutation types between crocidolite-induced mutations and spontaneous

mutations. Based on this the authors suggested that the molecular mechanism of crocidolite

differed from the generation of spontaneous mutations. The most frequent crocidolite induced

mutation (29%) was G to T transversions. In addition in rats given 1 or 2 mg of crocidolite the

levels of 8-Oxo-2'-deoxyguanosine in were increased in omenta (Unfried et al., 2002).

Mammalian cytogenic assays

Chrysotile was investigated in rhesus monkeys, mice. Oral dosage of 100 or 500 mg/kg bw did not

increase the level of chromosome aberrations in the monkeys. Oral or intraperitoneal dosing of 0.4

or 400 mg/kg bw of chrysotile was not associated with the induction of micronuclei formation in

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bone marrow cells in mice (Lavappa et al., 1975). Mice were intraperitoneally injected with 50

mg/kg /bw) of chrysotile and peritoneal cells were investigated and chromosome aberrations were

found to be increased (Durnev et al., 1993).

Crocidolite fibres were given to rats by gavage at 50 mg/kg bw in the presence or absence of

various concentrations of benzo[a]pyrene (0.25 to 2.5 µg/mL). Ames test was performed on

concentrated urine or serum samples of the treated animals: No effects were observed in this

assay. Formation of micronuclei and sister chromatid exchanges was studied in the bone marrow

of the rats, There was no effect of crocidolite alone, but effect on micronuclei in combination with

benzo[a]pyrene at 1 µg/mL and at in sister chromatid exchange in combination with all levels of

benzo[a]pyrene (Varga et al., 1996b).

Anthophyllite was orally administered to rats at 50 mg/kg (bw) in the presence or absence of

absorption of benzo[a]pyrene as an organic pollutant (0.25 to 2.5 µg/mL). In bone marrow samples

taken 24 h later, The combined exposure increased the sister chromatid exchange frequencies

(benzo[a]pyrene at 0.5, 1 and 2.5 µg/mL), something that was not seen for the fibre alone (Varga et

al., 1996a).

7.6.3. In vitro

We note that as asbestos are fibres, the value of in vitro investigations is questionable. This is

because fibres penetrate the tissues and cells inside the mammalian body - by a physical process;

and this mode of bio-distribution is not readily mimicked in vitro. Therefore we have not included

in vitro data on this endpoint in our assessment.

7.6.4. Conclusion on whether asbestos should be evaluated by non-threshold

mechanisms

There is some

in vivo

evidence that asbestos have cytogenic effects in the form of increased

frequency of chromosome aberrations and sister chromatid exchanges. Thus, a genotoxic effect at

the chromosome level is suggested. Furthermore, a number of studies have shown that asbestos

fibres have effects in mutagenic assays. Amosite induced mutations in an

in vivo

mammalian

mutagenicity assays, in one positive study. For crocidolite there are three positive studies and one

negative study. Overall, there is

in vivo

evidence for mutagenic effects of asbestos fibres.

The current working group recommends to comply with ECHA in REACH R8 (ECHA, 2012)

states the following: “Unless

a threshold mechanism of action is clearly demonstrated, it is generally

considered prudent to assume that thresholds cannot be identified in relation to mutagenicity, genotoxicity,

and genotoxic carcinogenicity, although a dose-response relationship may be shown under experimental

conditions”.

The decision tree is shown in fig 6. Based on this the current working group

recommends that asbestos fibres are hazard assessed using a numerical risk assessment based on a

linear approach and thus based on a notion that there is no threshold.

Notably our assessment is in line with both the EU (EU, 2009) and Afsset (Afsset, 2009) who

considers asbestos not to have a lower threshold. In the EU council directive 2009/148/EC it is

stated that: “Although

current scientific knowledge is not such that a level can be established below which

risks to health cease to exist, a reduction in exposure to asbestos will nonetheless reduce the risk of

developing asbestos related disease”;

and: “Even

though it has not yet been possible to identify the exposure

threshold below which asbestos does not involve a cancer risk, occupational exposure of workers to asbestos

should be reduced to a minimum”.

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7.7. Carcinogenicity

7.7.1. Human data (covering the period up to 2012 - based on IARC 2012)

All asbestos types are classified by IARC as having a carcinogenic potential for humans. There is a

classification of Category 1A in the European Union and Group 1 by the International Agency for

Research on Cancer (IARC, 2012). And asbestos was previously evaluated in 1987 and also

classified as Group 1 then (IARC, 1987). This section is based on (IARC, 2012).

There is a large body of epidemiological data pointing towards that asbestos induces

carcinogenicity (IARC, 2012). The main cancer forms associated with the exposure to asbestos are

lung cancer and mesothelioma. The latter primarily occurs in the pleura of the lungs, but it also

occurs in the peritoneum of the abdomen and in the pericardium of the heart. Notably there is a

latency period of 20-40 years in the development of these conditions. Lung cancer (broncho-

pulmonary cancer) is the first cause of mortality in asbestos exposed humans. The risk factor of

asbestos induced lung cancer is increased by simultaneous exposure to tobacco smoke. This

synergetic effect of tobacco smoke is not observed for mesothelioma. Concerning mesothelioma,

asbestos is the only proven risk factor although other risk factors have also been suggested

including infection with certain viruses and the exposure to ionising radiation. There is evidence

from epidemiological studies that exposure to the serpentine asbestos, chrysotile, is less potent in

the development of these cancers, in particular for mesothelioma, as compared to the amphibole

asbestos types. There is however a debate on whether this is the case lung cancer.

Based on IARC (IARC, 2012) the following cancers are described in the current section:

- Cancer of the lung

- Pleural and peritoneal mesothelioma

- Gastrointestinal tract cancers

- Cancer of the larynx

- Cancer of the ovary

These cancers form subdivisions of the next sections containing cohort- and case-control studies

The IARC evaluation from 2012 (IARC, 2012) gives an informative description of the data pointing

towards the different cancer forms. The following sections on cohort studies and case-control

studies are written based on this IARC 2012 evaluation.

Lung cancer

In IARC (IARC, 2012) it is described that the first reported signs of cancer of the lung induced by

asbestos in worker were reported already in 1935 (Gloyne, 1935; Lynch and Smith, 1935); and the

first cohort study to demonstrate excess cancer of the lungs among asbestos workers was a study

in textile workers published in 1955 (Doll, 1993). After that numerous cohort and case-control

studies were published demonstrating an association between cancer of the lungs and exposure to

asbestos (IARC, 2012).

IARC notes that still in 2012 (publication year of the IARC report), there were still substantial

controversies on how the risk might vary by exposure to different fibre types and sizes, and

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whether there is a risk at low levels of exposure (i.e. environmental exposure). And that a

particular controversy was whether chrysotile asbestos is less potent for the induction of cancer of

the lungs as compared to the amphibole asbestos types. This is what has been described as the

“amphibole hypothesis”. One of the reasons for this is a lower biopersistence of chrysotile as

compared to the amphiboles. But it is noted by IARC that a lower biopersistence of chrysotile does

not necessarily imply that it would be less potent for cancer of the lungs. IARC notes that a meta-

analysis by (Lash et al., 1997) based on findings in 15 cohort studies with quantitative information

on the relation between asbestos exposure and the risk of cancer of the lungs, did not find evidence

that differences in fibre type explained the heterogeneity of the data (IARC, 2012; Lash et al., 1997).

Another meta-analysis was conducted by (Hodgson and Darnton, 2000) and was based on 17

cohort studies. Substantial heterogeneity in the data was also found in this study. This

heterogeneity was largely attributable to differences in the findings from the studies of chrysotile

miners and millers in Quebec (McDonald et al., 1983) and asbestos textile workers in South

Carolina (Dement and Brown, 1994; Hein et al., 2007). No definite explanation for these differences

was found, although the co-exposure to mineral oils in the South Carolina textile plant was

proposed as an explanation. Increased fibre length in the textile industries was also suggested as

an explanation, as compared to exposure to shorter fibres of the miners and millers in Quebec.

Ratios between lung cancer risk for chrysotile and the amphiboles are in the range of 1:2 to 1:50

depending on which studies that are excluded.

A meta-analysis was published by Berman and Crump in 2008 (Berman and Crump, 2008a), and

lung cancer risk potency factors derived in their analyses were specific for both fibre types

(chrysotile

vs.

amphiboles) and fibre size (length and width). For this fibres there was evidence

that chrysotile fibres were less potent than amphiboles. Exclusion of the South Carolina cohort

from the analysis resulted in in a highly significant result that the potency was greater for

amphiboles than for chrysotiles; exclusion of the Quebec study resulted in that there was no

evidence of differences in-between the fibre types. Considering fibre size, there was only weak

evidence in Berman and Crump that long fibres (>10 µm) were more potent than short fibres (5

µm<length<10 µm) in models using all widths (p=0.07). It is noted by IARC that there was a lack of

size specific data.

Stayner

et al.

(Stayner et al., 2008) analysed the South Carolina asbestos textile cohort using size

information established from reanalysis of archived air samples by (Dement et al., 2008). Long

fibres (>10 µm) and thin ones (<0.25 µm) were found to be the strongest predictors of lung cancer

in that study. Loomis et al (Loomis et al., 2010) did a retrospective cohort study in workers from 4

plants in North Carolina that had never been studies before. The workers in these plants were

primarily exposed to asbestos that was imported from Quebec. IARC notes that a small amount of

amosite was used in an operation at one of the plants. Overall and standardised mortality ratio

(SMR) of cancer of the lung was 1.96 (95% confidence interval (CI): 1.73 to 2.20) noted by IARC to

be similar to that reported in the South Carolina study (Hein et al., 2007), although the slope for the

dose-response curve was considerably lower than that reported for the South Carolina cohort

study.

Concerning environmental exposures, IARC reports that there is evidence for an association

between cancer of the lungs and environmental exposures in New Caledonia to field dust

containing tremolite and the use of a so-called whitewash (“po”) containing tremolite (Luce et al.,

2000). Also a positive association with heavy residential exposure to asbestos was reported in a

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lung cancer case-control study from the crocidolite and amosite mining area of the Northern

Province of South Africa (Mzileni et al., 1999). Concerning negative data, there was no increase in

lung cancer of women in the Quebec mining regions as compared to women from other areas of

Canada (Camus et al., 1998).

IARC also discusses that there is emerging evidence that non-commercial amphibole fibres that

are asbestiform have a carcinogenic potential. These are not technically “asbestos”. Amphibole

fibres that contaminated vermiculite mined in Libby Montana USA. These were originally

characterised as from the tremolite-actinolite series, but have later been described by the US

Geological Society as approximately 84% Winchite, 11% Richterite, and 6% tremolite. For these

fibres there was an increased SMR for all cancers as well as lung cancer (Sullivan, 2007).

Mesothelioma

According to IARC the first reports on asbestos exposure and mesothelioma was by (WAGNER et

al., 1960). Here an outbreak of mesothelioma occurred in a crocidolite mining region of South

Africa 23 out of 33 of the cases had worked in the mines but the remaining 10 had no history of

occupational exposure to crocidolite. A large number of subsequent studied have reported excess

mesothelioma in both cohort and case-control studies (IARC, 2012).

Concerning fibre types,

all types have been described to cause mesothelioma, but there is

evidence that chrysotile is less potent than the amphibole types. This was found in cohort studies

of chrysotile exposed miners and millers in Quebec (Liddell et al., 1997) and in the South Carolina

textile workers who were predominantly exposed to chrysotile asbestos from Quebec (Hein et al.,

2007). IARC notes that the fact that chrysotile from Quebec is contaminated with a small amount

(<1%) of the amphibole tremolite, however, should be taken into account when interpreting these

data. It was found that there was an association between mesothelioma and asbestos in an area

that had higher tremolite concentrations in the asbestos, and that this association was not found in

a region where the amount of tremolite was lower (McDonald et al., 1997). However this difference

could also be explained in differences in the sizes of the workforce at the two sites (Bégin et al.,

1992), and in a separate analysis of the workers at mines and mills in this area that was no

difference in exposure-relationship for asbestos and mesothelioma in the two mining areas

(McDonald and McDonald, 1995). In case-control study for mesothelioma in South Africa there

was a an association with exposures to crocidolite and amosite, whereas no cases were found to

have been exclusively exposed to chrysotile (Rees et al., 1999). One explanation for this could be

that there is only little contamination of chrysotile with tremolite – in South Africa (Rees et al.,

1992), or that chrysotile mining began later and production levels were lower in South Africa, and

that in Zimbabwe cases of mesothelioma was reported from chrysotile asbestos not contaminated

with tremolite (Cullen and Baloyi, 1991). Excess mortality from mesothelioma was reported in

miners and millers from a chrysotile mine in Balangero, Italy that was reported to not be

contaminated with amphibole (Piolatto et al., 1990).

Hodgson and Darnton studied mesothelioma deaths and estimated a ratio of the potency for

mesothelioma to be 1:100:500 for chrysotile, amosite and crocidolite, respectively (Hodgson and

Darnton, 2000). A meta-analysis was conducted by (Berman and Crump, 2008b, 2008a) a

hypothesis that chrysotile and amphibole types were equipotent was strongly rejected. And they

could not reject a hypothesis that the relative potency of chrysotile was zero, and found that the

best estimates for the relative potency of chrysotile ranged from zero to about 1/200

that of

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amphibole asbestos. However, IARC notes that there is a high degree of uncertainty concerning

the accuracy of these relative potency estimates from Berman and Crump.

IARC reported two studies not included in the previously described meta-analyses. The first

was in a cohort in North Carolina (Loomis et al., 2010). The workers were predominantly exposed

to chrysotile imported from Quebec. They had a SMR for mesothelioma of 10.9 (95% CIl: 3.0 to

28.0); and for pleural cancer the SMR was 12.4 (95 CI: 3.4 to 31.8). In addition, Stayner

et al.

estimated that the percentage of deaths per unit of fibre exposed was 0.0058% per fibre-year/mL

(Stayner et al., 1996). Whereas, Hodgson and Darnton described previously estimated 0.0010% per

fibre-years/mL for cohorts exposed to chrysotile. In an additional study concerning Balangero in

Italy, an area in which the mined chrysotile is reported to be free of tremolite and other

amphiboles, six cases of mesothelioma were identified among blue-collar miners. Additional cases

of mesothelioma were identified among white-collar miners (3 cases), workers in the mine hired by

subcontractors (5 cases) and from non-occupational exposures or exposures to re-used tailings (10

cases) (Piolatto et al., 1990).

Concerning fibre sizes,

There is only weak evidence for an effect of fibre size on mesothelioma in

humans (Lippmann, 1990).

Concerning environmental exposures,

Excess mesothelioma has been reported in: villages in Turkey

exposed to erionite that was used to whitewash their homes (Baris et al., 1987), in people living

near crocidolite mining regions in South Africa and Western Australia (Wagner and Pooley, 1986),

among people residing in areas of tremolite contamination in Cyprus (McConnochie et al., 1987)

and New Caledonia (Luce et al., 2000) and after non-occupational exposures in Europe (Magnani

et al., 2000), Italy (Magnani et al., 2001) and California (Pan et al., 2005). Also, mesothelioma has

been reported to occur among household members of families of asbestos workers (Anderson et

al., 1976; Ferrante et al., 2007).

Concerning non-commercial fibres,

like for lung cancer there are positive findings for amphibole

fibres that contaminated vermiculite mine in Libby Montana, U.S. The SMR for mesothelioma was

14.1 (95% CI: 1.8 to 54.4) and the SMR for pleural cancer was 23.3 (95% CI: 6.3 to 59.5) (McDonald

et al., 2004). Also the exposure to fluoro-edenite a fibre similar in morphology and composition to

the tremolite actinolite series has been reported to be associated to mesotheliomas (IARC, 2012).

Other cancer sites

IARC notes that the literature on the association of asbestos and other forms of cancer is sparse in

comparison to that for lung cancer and mesothelioma. IARC describes cohort studies and case-

control studies investigating the associations between exposure to asbestos and the following

cancers (IARC, 2012):

a) Cancer of the pharynx

b) Cancer of the larynx

c) Cancer of the oesophagus

d) Cancer of the stomach

e) Cancer of the colorectum

f) Cancer of the ovary

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Concerning a) to e), IARC bases its text on a report published by the Institute of Medicine IOM

(IOM, 2006). Concerning f) cancer of the ovary, IARC has gathered the data themselves. After a

section on each of these cancers IARC has a “Synthesis chapter”. In the current document we base

the text on this particular “Synthesis chapter”.

IARC wrote that a causal association between exposure to asbestos and cancer of the larynx was

clearly established but that with the current data there is insufficient information to discern

whether any differences exist among fibre types. The IARC working groups noted that a causal

association between exposure to asbestos and cancer of the ovary was clearly established. The

IARC working group noted a positive association between exposure to asbestos and cancer of the

pharynx. The IARC working group noted a positive association between the exposure to asbestos

and cancer of the stomach. The IARC working group noted a positive association between the

exposure to asbestos and cancer of the colorectum (IARC, 2012).

Summary

There is evidence from studies on humans that asbestos causes cancer of the lung, pleural and

peritoneal mesothelioma, gastrointestinal-tract cancers, cancer of the larynx, and cancer of the

ovary. Concerning risk levels as function of exposure we discuss this in section 7.7.4. – the section

of carcinogenic risk assessment.

7.7.2. Human data after IARC 2012

The IARC monograph was published in 2012 (IARC, 2012), the Afsset report was published in 2009

(Afsset, 2009) and the DECOS report in 2010. Therefore we reviewed the literature published

during the period of 2008 to 2019. This review includes epidemiological studies of asbestos

exposure and the induction of lung cancer/mesothelioma. In reviewing the identified articles we

focussed on studies that provide dose-response estimates. These are presented in detail (the next

section), whereas other studies are only shortly mentioned.

Studies in which exposure levels were addressed

A study by Van der Bij

et al.

was identified (van der Bij et al., 2013). This study is presented in

section 7.7.4. the section: “Carcinogenic risk assessment”.

Deng

et al.

and Courtice

et al.

in two separate articles evaluated the same cohort of Chinese

workers that had been exposed to chrysotile at a textile factory (Courtice et al., 2016; Deng et al.,

2012). Deng

et al.

in 2012 had 586 workers in the cohort. The workers were followed from 1972 to

2006. Air sample measurements from the workshops were used to convert dust concentrations to

fibre concentrations. The estimated asbestos fibre concentration in the study factory was 13.8

fibres/mL. Individual cumulative asbestos exposure was estimated as the product of fibre

concentrations and duration of employment in each job and expressed as fibre-years/mL. The vital

status of cohort members was followed annually. Poisson regression analysis was applied to fit

log-linear, log-quadratic, power, additive relative risk (RR) and categorical models to estimate

exposure response relationships between cumulative fibre exposure and mortality from lung

cancer and asbestosis. Out of 226 deaths over the 35-year follow-up, 51 were from lung cancer and

37 from asbestosis. A significant exposure-response relation with either lung cancer or asbestosis

was observed. A power model with lagged 10 years was found to be the best model of those

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evaluated for both lung cancer and asbestosis (Deng et al., 2012). The current working group notes

that comparison between the risk obtained in this article and those of the reports by DECOS and

Afsset described later in this report is difficult. Difficulties to comparison to the results on life-time

cancer risk in the DECOS and Afsset reports stems from 1) difficulty to estimate the life time risk

from “per 100 person-years”; and 2) no reporting in the Deng article of lung cancer risk in a

comparable control population.

The cohort was reinvestigated in 2016 by Courtice

et al.,

however, in this study no lung

cancer risk base level was given. Only the hazard ratio was reported and found to be increased for

both lung cancer and asbestosis (Courtice et al., 2016).

Larson

et al.

conducted an exposure-response study to obtain estimates of the hazard of

asbestos-related mortality association with cumulative asbestos exposure. The study cohort was

the so-called vermiculite worker cohort reconstructed by the Agency for Toxic Substances and

Disease Registry (ATSDR). The number of workers was 1862; the workers were exposed to Libby

amphibole. Historical air sampling data were used to estimate the 8-hour TWA fibre exposure for

all areas of the vermiculite operation for various time periods in the company’s history. The

proportion of each day spent at each location was calculated for each job title, and an 8-hour TWA

exposure was estimated for each job at a given time. Cumulative fibre exposures for each job that a

worker held was estimated by weighting the 8-hour TWA exposure for a given job held by the

worker by length of time spent at that job. Finally, lifetime cumulative fibre exposures for each

worker was obtained by summing the cumulative fibre exposures for each job that worker held.

The SMR of mesothelioma was 94.8 (95% CI: 57.0–148.0); of Malignant neoplasms of the bronchus

or lung: 1.6 (95% CI: 1.3–2.0) and of asbestosis: 142.8 (95% CI: 111.1–180.8). The estimated RR was

given for certain categories of exposure levels (below 1.4; 1.4 to 8.6; 8.6 to 44; and above 44

fibres/mL-year) demonstrating dose-responsiveness for mesothelioma, asbestosis and lung cancer

(data not included here), but no dose response curve was established (Larson et al., 2010). Due to

the use of exposure categories a calculation into extra cancer risk, for comparison to the DECOS

and Afsset reports (described later in this report), is not readily done.

Wang

et al.

studied the relation between mortality from lung cancer and other selected causes

to asbestos exposure levels. A cohort of 1,539 male workers from a chrysotile mine in China was

followed for 26 years. Data on vital status, occupation and smoking were collected from the mine

records and individual contacts. Causes and dates of death were further verified from the local

death registry. Individual cumulative fibre exposures (fibre-years/mL) were estimated based on

converted dust measurements and working years at specific workshops. SMRs for lung cancer,

gastrointestinal cancer, all cancers and non-malignant respiratory diseases stratified by

employment years, estimated cumulative fibre exposure, and smoking were calculated. Poisson

models were fitted to determine exposure-response relation between estimated fibre exposures

and cause-specific mortality, adjusting for age and smoking. In conclusion there were clear

exposure-response relationships in this cohort, which imply a causal link between chrysotile

asbestos exposure and lung cancer and non-malignant respiratory diseases, and possibly to

gastrointestinal cancer, at least for smokers (Wang et al., 2013).

Data on asbestos environmental concentrations in Thetford Mines, a mining city in Quebec,

Canada, provided an opportunity to undertake a prospective cancer risk assessment in the general

population exposed to these concentrations. Using an updated Berman and Crump dose-response

model for asbestos exposure, Bourgault

et al.

selected population-specific potency factors for lung

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cancer and mesothelioma(K

and K

values

), and these were multiplied by a factor of 4.2 to

account for the difference in exposure duration between workers (40 h/week) and the general

population (168 h/week). These factors were evaluated on the basis of population-specific cancer

data attributed to the studied area's past environmental levels of asbestos. Also employed were

more recent population-specific mortality data along with the validated potency factors to

generate corresponding inhalation unit risks. These unit risks were then combined with recent

environmental measurements (range in outdoor air: 0.0015 to 0.056 fibres/mL; range in indoor air:

0.00055 to 0.01) made in the mining town to calculate estimated lifetime risk of asbestos-induced

lung cancer and mesothelioma. Depending on the chosen potency factors, the lifetime mortality

risks varied between 0.7 and 2.6 per 100,000 for lung cancer and between 0.7 and 2.3 per 100,000

for mesothelioma. In conclusion, the estimated lifetime cancer risk for both cancers combined – for

the general population - was close to Health Canada's threshold for "negligible" lifetime cancer

risks (i.e. 1:100 000) (Bourgault et al., 2014).

Other studies

A number of studies support that asbestos exposure is associated with lung cancer (Boffetta et al.,

2019; Cole et al., 2013; Elliott et al., 2012; Ferrante et al., 2017; Hamra et al., 2017, 2014; Järvholm

and Aström, 2014; Ngamwong et al., 2015; Offermans et al., 2014a; Villeneuve et al., 2012; Wu et

al., 2015). And a number of studies support the association with mesothelioma (Boffetta et al., 2019;

Ferrante et al., 2017, 2016; Lacourt et al., 2014; Langhoff et al., 2014; Markowitz et al., 2013; Oddone

et al., 2017; Offermans et al., 2014a; Pira et al., 2017; Plato et al., 2016; Reid et al., 2014; Van den

Borre and Deboosere, 2014). And the association between asbestos exposure and mortality (Repp

et al., 2015); and the association of asbestos exposure with gastrointestinal cancer (Fortunato and

Rushton, 2015; Li et al., 2016; Offermans et al., 2014b; Peng et al., 2015; Wu et al., 2015); laryngal

cancer (Offermans et al., 2014a); and ovary cancer (Ferrante et al., 2017)

Summary

The literature from the period after the 2012 IARC evaluation provides further evidence from

epidemiological studies that asbestos causes cancer of the lung, pleural and peritoneal

mesothelioma, gastrointestinal-tract cancers, cancer of the larynx, and cancer of the ovary. The Van

Den Bij 2013 study provides a number of extra lung cancer cases after asbestos exposure that is

comparable to the risk levels obtained by DECOS and presented below in section 7.7.4. – the

section of carcinogenic risk assessment.

7.7.3. Animal data

Inhalation

For the inhalation studies, we reviewed animal studies and determined the mass concentrations

and fibre concentrations at which the number of animals with neoplasms was increased. In

addition we determined the next lower level – the highest level at which the number of animals

with neoplasms was not increased (Figure 6). These numbers help determine concentrations at

L(Lung cancer)

and K

M(mesothelioma)

values are the slope of a straight line when cancer risk is plotted as function of

exposure. The concept is explained in detail in Section 7.7.4.

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which carcinogenicity can be observed. In the section below we describe the animal studies

underlying the values in Figure 6.

Mass concentrations of tumour induction

100

Mass concentration (mg/m

)

Davis 1988, Rat Davis 1985, Rat

Wagner 1974, Rat, also shorter time periods

Hesterberg 1998, Rat

Davis 1991, Rat

Davis and Jones 1988, Rat

Davis 1986, Br. J. Exp. Path p113 study, Rat

Davis 1978, Rat

1000

2000

3000

4000

Time (h)

Chrysotile Conc tumours

Amosite Conc No tumours

Amosite Conc tumours

Crocidolite Conc No tumours

Crocidolite Conc tumours

Anthophyllite Conc tumours

Tremolite Conc tumours

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Fibre concentrations of lung tumour induction

100000

Fibre concentration (Fibres/cm

)

10000

Davis 1988, Rat

Hesterberg 1998, Rat

Davis and Jones 1988, Rat, long sample

Davis 1991, Rat

Davis 1986, Br. J. Exp. Path p415 study, Rat long fibres

Davis 1985, Rat

Davis and Jones 1988, Rat, short sample

Davis 1978, Rat

1000

100

Davis 1986, Br. J. Exp. Path p113 study, Rat

Davis 1986, Br. J. Exp. Path p415 study, Rat short fibres

1000

2000

3000

4000

Time (h)

Chrysotile Conc tumours

Amosite Conc No tumours

Amosite Conc tumours

Crocidolite Conc No tumours

Tremolite Conc tumours

Figure 6. Mass concentrations and fibre concentrations at which carcinogenicity is absent or

present.

Upper panel Mass concentrations; Lower panel: Fibre concentrations.

Studies that compare chrysotile,

amosite,

anthophyllite, and crocidolite

Rats inhaled amosite, anthophyllite, crocidolite, Canadian chrysotile or Rhodesian chrysotile. The

mass concentrations varied somewhat over a 2 year period (7h/day 5 days/week) (up to 3640 h).

The mean respirable dust concentration at 24 months was reported to be 10.6 (amosite and

anthophyllite), 10.3 (crocidolite) and 10.1 mg/m

(the two forms of chrysotile). Cumulative doses

were in the range of 33200 to 33600 (mg/m

hours). For the amphiboles amosite, anthophyllite and

crocidolite there was an increase of lung dust with dose (dose was increased in the sense of

differences in exposure time), whereas for the chrysotile much less dust was observed in the lungs.

The amount of dust in lungs decreased after removal of exposure at 6 months with a recovery time

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up to an additional 18 months. The number of rats with lung tumours were Control 7/126 (7 rats

out of a total of 126 animals in the group); amosite: 38/146, anthophyllite 50/145, crocidolite: 55/141,

Chrysotile (Canadian): 45/137; Chrysotile (Rhodesian): 59/144. The number of rats with

mesotheliomas were Control 0/126 (7 rats out of a total of 126 animals in the group); amosite: 1/146,

anthophyllite 2/145, crocidolite: 4/141, Chrysotile (Canadian): 4/137; Chrysotile (Rhodesian): 0/144.

There were also tumours in breast, pituitary and other sites, and survival times were also reported.

Concerning the concentration at which tumours occurs this is not readily evaluated as there were

exposure times lower than 24 months and up to 24 months (Concentration

tumours observed

: 10.6

(amosite and anthophyllite), 10.3 (crocidolite) and 10.1 mg/m

(the two forms of

chrysotile))(fibres/cm

not given) (Wagner et al., 1974). In an extension of this study, mast cell

numbers were investigated and found to be increased along with increased exposure. And mast

cell numbers were also associated to increasing subpleural thickening (Wagner et al., 1984).

Chrysotile, crocidolite, amosite

Rats inhaled chrysotile, crocidolite, or amosite at 2 or 10 mg/m

(chrysotile), 5 or 10 mg/m

(crocidolite) or 10 mg/m

for amosite for 7h/day 5 days/week for 12

months (1568 h) (fibre numbers were 390 and 1950 fibres/cm

for chrysotile (>5 µm), and 430 and

860 fibres/cm

for crocidolite and 550 fibres/cm

for amosite). There is also recovery of asbestos in

lungs 7 and 182 days. Fibrosis was most pronounced for chrysotile than it was for the amphibole

asbestos types, crocidolite or amosite. Malignant pulmonary tumours were only observed

following chrysotile. This was reported to have a possible explanation of a longer fibre length

(Chrysotile Concentration

tumours observed

: 2 mg/m

/ 390 fibres/cm3; Crocidolite Concentration

No tumours

observed

: 10 mg/m

/ 860 fibres/cm

; Amosite Concentration

tumours observed

: 10 mg/m

/ 550 fibres/cm

)

(Davis et al., 1978).

Chrysotile, amosite

Rats inhaled chrysotile alone, amosite alone or a mixture of amosite or chrysotile

that was added either TiO

or quartz. The mass concentration was ~10 mg/m

of asbestos (plus in

some cases: ~10 mg/m

dust) and the exposure period was for 1 year at 7h per day. But the number

of days per week was not reported but estimated to be 5 days (~1820 h), with a 2-year follow-up.

The addition of quartz (but not TiO

) increased the level of fibrosis in comparison to the level

observed with the fibres alone. Exposure to both quartz and TiO

asbestos mixtures were

associated with increased numbers of pulmonary tumours and mesotheliomas as compared to

only asbestos exposure. However both chrysotile and amosite had increased number of animals

with tumours as compared to control (Chrysotile Concentration

tumours observed

: 10 mg/m

/ 2560 fibres

(>5 µm)/cm

) (Amosite Concentration

tumours observed

: 10 mg/m

/ 2060 fibres (>5 µm)/cm

) (Davis et al.,

1991).

Studies on only chrysotile

Rats were exposed to either normally charged or discharged chrysotile asbestos at 10 mg/m

for

7h/day 5days/week for 1 year (1568 h). Recovery periods were the full life time of the animals.

Normally charged chrysotile produced the highest level of pulmonary fibrosis and a higher

number of pulmonary tumours – but the difference to discharged seems not to be statistically

significant (Concentration

tumours observed

: 10 mg/m

/ 2560 fibres (>5 µm)/cm

) (Davis et al., 1988). Rats

It is unknown whether the article states the number of animals with tumours or the total number of

tumours of all the animals.

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inhaled chrysotile at 10 mg/m

, 7h/day, 5 days/week for 1 year (1820 h). The chrysotile asbestos

was either a short (1170 fibres (>5 µm)/cm

) or a long fibre length sample (5510 fibres (>5 µm)/cm

The 1 year study period was followed by a 6, and 14 to 18, month recovery periods. At the end of

the inhalation exposure period the elimination rate of short chrysotile fibres was higher than that

observed for long fibres. Rats exposed to the long-fibre chrysotile exhibited what was described as

“a more advanced interstitial fibrosis (asbestosis)” and more pulmonary tumours as compared to

rats exposed to the short-fibre sample; Although both fibre lengths induced increased numbers of

tumours as compared to control - as evaluated by Fischer’s exact test performed by us.

(LOAEC

fibrosis

in the inhalation study: 10 mg/m

) (Short sample Concentration

tumours observed

in the

inhalation study: 10 mg/m

/ 1170 fibres (>5 µm)/cm

; Long sample Concentration

tumours observed

: 10

mg/m

/ 5510 fibres (>5 µm)/cm

) (Davis and Jones, 1988).

Rats were exposed to chrysotile fibres by nose-only inhalation at 10 mg/m

for 6 h/day, 5

days/week for 2 years (3120 h). After this exposure there was a recovery period of 23 weeks. But

rats were also euthanized directly after 13, 26, 39, 52, 78, and 104 weeks of exposure. Thoracic

neoplasms and pulmonary fibrosis were observed after exposure to the fibres as compared to

controls, as were chronic inflammation, bronchoalveolar hyperplasia and collagen deposition

(LOAEC

fibrosis

10 mg/m

) (Concentration

tumours observed

10 mg/m

3 16

, and 10600 WHO fibres (5 µm in

length and >3 µm in diameter)/cm

) (Hesterberg et al., 1998).

Rats were exposed by inhalation to a) yarn form wet dispersed chrysotile production process,

b) dust collected from the factory air in a workshop processing only this type of wet dispersed

chrysotile, c) a standard chrysotile textile yarn produced by traditional methods, or d) yarn from

another chrysotile wet dispersion process. The mass concentrations were 3.5, 3.7, 3.5 and 3.5, for

these groups, respectively (fibre numbers: 679, 468, 428, and 108 fibres/mL). The duration was

7h/day, 5 days/week for a total of 224 days over a period of 12 months (1568 h). Exposure to the

samples resulted in all groups in fibrosis and carcinogenicity with no intergroup differences.

Pulmonary carcinomas developed in 25% of the animals and in what was designated as advanced

interstitial fibrosis was observed in (on average) 10% of all lung tissue. In a subsequent

intraperitoneal injection study, rats were administered a dose of 25 mg/rat. This exposure resulted

in all fibre dosed groups in mesotheliomas in more than 90% of the rats (Concentration

tumours observed

chrysotile yarn c) 3.5 mg/m

) (Davis et al., 1986a).

Studies on only amosite

Rats inhaled 1000 fibres (longer than 5 µm)/mL, 7 h/day, 5 days/week for 12 months (1820 h).

Fibrosis was observed. Concerning tumours, out of 42 exposed rats, 16 had lung tumours (7 had

carcinoma, 9: adenoma) and 2 mesotheliomas were observed. Of 38 controls, two had lung

tumours and none mesothelioma (no mass concentration was reported; Fibre concentration

tumours

observed

: 1000 fibres/cm

) (Cullen et al., 2000). Rats inhaled amosite of short or long length. The mass

concentration was 10 mg/m

and the duration was 7h/day for 5 days/week for a total of 224 days

during a 12 month period (1568 h). The short fibres were almost all shorter than 5 µm (70 fibres (>5

µm)/cm

). The long fibres consisted of dust prepared from raw amosite (2060 fibres (>5 µm)/cm

Exposure to the long fibre resulted in pulmonary fibrosis, and in one third of the animals,

pulmonary tumours or mesotheliomas. These effects were not observed following the exposure to

In the article only the total number of tumours is given, not the total number of animals with tumours.

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short fibres. (Concentration

tumours observed

short fibre 10 mg/m

/ 70 fibres (>5 µm)/cm

Concentration

tumours observed

long fibre 10 mg/m

/ 2060 fibres (>5 µm)/cm

) (Davis et al., 1986b).

Studies on only tremolite

Rats inhaled tremolite at 10 mg/m

for 7 h/day 5 days/week for 12 months (1568 h) and exhibited

pulmonary fibrosis. In addition 16 cases of carcinogenesis was observed out of 39 animals as

compared to no cases in 36 controls (Concentration

tumours observed

: 10 mg/m

/ 1600 fibres (>5 µm)/cm

)

(Davis et al., 1985).

Intratracheal instillation

In light of the high number of inhalation studies in animals and in light of the amount of human

data intratracheal instillation studies were not considered for this endpoint.

Dermal application

Crocidolite and amosite both contain oils and also during processing, transport and storage

asbestos is sometimes contaminated with such oils as jute oil. In one study both natural and

contaminating oils were isolated and tested for their tumour initiating properties. Mice were

exposed twice weekly with co-exposure to croton oil (a tumour promoting agent). Increased cases

of papillomas for both asbestos types as well as increased carcinomas in the case of amosite were

observed (Roe et al., 1966).

Oral application

Chrysotile at either short range or intermediate range was administered to Syrian golden hamsters.

The dose was a concentration of 1% in pelleted diet for the whole lifetime of the hamsters, starting

with mothers of the test animals. There was no adverse effect on body weight gain or survival by

either fibre length. An increase in adrenal cortical adenomas was observed in male hamsters

exposed to short range and intermediate range chrysotile and in females treated with intermediate

range chrysotile asbestos when compared to the pooled control groups (males: pooled controls,

25/466, 5%; short range chrysotile, 26/299, 11%; intermediate range chrysotile, 24/244, 10%; females:

pooled controls, 15/468, 3%; intermediate range chrysotile, 18/234, 8%). However, statistical

significance was lost when these dosed groups were compared with concurrent control groups

(males: short range control, 7/115, 6%; intermediate range control, 7/115, 6%; females: short range

control, 4/112, 4%; intermediate range control, 6/118, 5%). Neither short range chrysotile nor

intermediate range chrysotile asbestos was carcinogenic when ingested at 1% levels in the diet by

male and female Syrian golden hamsters. Whereas there were increases in the rates of adrenal

cortical adenomas in male and female hamsters exposed to intermediate range chrysotile asbestos

compared to the pooled groups, these incidence rates were not different when compared with the

concurrent control groups. Additionally, the authors of that study suggested that the biologic

importance of adrenal tumours in the absence of target organ (gastrointestinal tract) neoplasia is

questionable (National Toxicology Program, 1990). Rats were given chrysotile at 1% in the diet. In

one study, 6 out of 10 of the rats developed malignant tumours, as compared to 1 out of 10 in the

control group. Nevertheless, in a second study, 11 out of 20 rats developed malignant tumours but

both in the treated and control group (Cunningham et al., 1977).

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Summary of animal data on carcinogenicity

Concerning the inhalation of asbestos carcinogenicity was observed at a mass concentration of 2

mg/m

and above. When presenting the data as fibre concentration the carcinogenicity has been

described already at 108 fibres/mL (Davis et al., 1986a). The studies showing carcinogenicity at the

lowest fibre numbers (Davis et al., 1986a, 1978; McConnell et al., 1999) are further used to calculate

human risk levels in the section of carcinogenic risk assessment (section 7.7.4.).

Some potential for carcinogenicity after dermal co-exposure of asbestos and croton oil cannot

be excluded. Also, animal data suggest a carcinogenic potential of asbestos after oral exposure.

7.7.4. Carcinogenic risk assessment

As human data from exposed workers are available, a numerical carcinogenic risk assessment

should be based on an aggregation of such data.

The current working group concludes that the hazard assessment critical endpoint is the

development of cancer, and that a non-threshold mechanism cannot be ruled out. In this section

the current working group discusses the evidence for setting risk estimates based on human data,

but also calculate estimates based on animal data for comparison.

Concerning the structure of this section, we first present the evaluations done by DECOS; Afsset,

and BAuA for the Netherlands, France and Germany. In addition, data from a study from Van der

Bij

et al.

is presented. After that, we provide a calculation based on animal data that we reviewed.

Finally we provide a section with our conclusions with our recommended risk estimates to be used

for the setting of a health-based OEL.

DECOS

Short summary of the DECOS report

The document called “Asbestos Risk of environmental and occupational exposure” from DECOS

(Dutch Expert Committee on Occupational Safety), concerns the risks associated with occupational

exposure to asbestos (DECOS, 2010). In the report, DECOS calculates values corresponding to the

risk levels defined in the context of environmental and occupational health policy. The values were

calculated on the basis of a meta-analysis, for which a selection of epidemiologic studies was made

using predefined inclusion criteria.

K values

were calculated for both lung cancer and mesothelioma. K

values for lung cancer

and K

values for mesothelioma. A weighed K

value was calculated based on 4 out of 18 available

cohort studies. No difference was found between chrysotile and the amphibole types. Concerning

mesothelioma a clear difference was observed in carcinogenic potential between chrysotile and the

The K

value is the increase in lung cancer risk per fibre-year of exposure (often reported as 100x KL); A

represents mesothelioma. For example, given a cumulative exposure of 100 years, a K

value of 0.01 will

result in a doubling of the relative risk of lung cancer.

The lung cancer risk, as established in cohort studies, is usually expressed as relative risk (RR). This is

risk in the exposed population divided by the risk in the non-exposed population (the general population or

a control group). RR and K

are related according to the formula: RR=1+K

x f x d, where f x d = cumulative

exposure in fibres/mL x years and K

is the carcinogenic potential in (fibres/mL x years)

-1

. This corresponds

to the mathematical formula for a straight line Y = b + aX.

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amphiboles. Therefore two separate K

values were calculated - one for each general asbestos type

(chrysotile

vs.

amphiboles). For their meta-analysis, DECOS, selected 2 out of 12 available cohort

studies, and calculated K

values for chrysotile as well as a mixture of chrysotile and up to 20%

amphibole. Also, a K

value was calculated for 100% amphibole. The calculated K

values

indicated that amphiboles were 50 times more potent than chrysotile in terms of carcinogenic

potential (mesothelioma).

The risk for occupational exposure was as detailed in Table 7 (DECOS, 2010):

Table 7. Exposure levels by asbestos type for mesothelioma and lung cancer combined,

corresponding to risk levels of 4.10

-3

and 4.10

-5

The values are for occupational exposure (eight

hours per day, five days per week, for a period of forty years) and are expressed

in fibres per m

(with fibres/mL between brackets), as measured by transmission electron

microscopy (TEM) (DECOS, 2010).

Review of the methods and studies employed by DECOS

DECOS’ assessment of a recent [recent in 2010] meta-analysis

DECOS reviewed an analysis by Hodgson and Darnton published in 2000 (Hodgson and Darnton,

2000); and also one by Berman and Crump from 2003 that was re-analysed in 2008 (Berman and

Crump, 2008a, 2003). DECOS noted that neither of these studies involved the selection of studies

on the basis of their quality. Also, DECOS reported that they did not agree with Hodgson and

Darnton who chose not to anchor the dose-effect line at an intercept of a (RR) of 1. And for a

number of studies this resulted in very high intercepts of more than 2 in RR, or of 200 in SMR.

DECOS notes this would imply that at zero exposure, the mortality from lung cancer in the

occupational population is more than double that seen in the general population. DECOS noted

that it is normal to extrapolate to low exposure levels, near the point where the cumulative

exposure is zero - and the RR is 1 (or the SMR is 100). DECOS accordingly recalculated the K

using linear regression with fixed intercept (α=1) values for all cohorts.

Concerning mesothelioma: DECOS wrote that:

“Hodgson and Darnton’s meta-analysis is in

principle usable in relation to mesothelioma; however, the authors use so-called R

values, which are

calculated differently and therefore vary from the K

values more commonly employed. Although there is

close correlation between the two indicators, direct comparison is not possible. Where mesothelioma is

concerned, the Committee has therefore recalculated K

values and choose not to use R

values calculated by

Hodgson and Darnton.”

DECOS notes that in view of these reservations, and especially concerning not selecting

studies for inclusion on the basis of exposure data quality, the Dutch Committee decided that new

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meta-analyses should be performed, both of the data linking asbestos with lung cancer and those

linking it with mesothelioma.

(New meta-analysis performed by DECOS

The meta-analysis was conducted according to a previously published protocol (Vlaanderen et al.,

2008). The meta-analysis performed by DECOS was published in the peer reviewed literature

(Lenters et al., 2011). This latter article subsequently spurred criticism by Berman and Case – a

criticism that was rebutted by Lenters

et al.,

who argued for the use of the truncated data set, in

which poorer-quality studies were excluded (Lenters et al., 2012).

DECOS’ meta-analysis of lung cancer

For the meta-analysis, DECOS searched the PubMed database for the period of 1950 to 2009 for

studies with quantitative estimates of cumulative asbestos exposure and lung cancer mortality and

identified original epidemiological studies. Most of these studies were already included in in the

analyses by Hodgson and Darnton (Hodgson and Darnton, 2000) and Berman and Crump 2008

(Berman and Crump, 2008a). A number of these studies were excluded and a total of 18 studies

were selected and included 17 cohort studies and 1 population-based case referent study (DECOS,

2010). DECOS’ calculated K

values are presented in Table 8.

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Table 8. Fibre type, production method, 100×K

L 18

value and standard error (SE) for each of the

studies considered for the meta-analysis (of which 18 were ultimately included).

The 100×K

values marked* with an asterisk were obtained using weighted linear regression; the others using

Poisson (DECOS, 2010).

These 18 studies were next assessed by the DECOS panel members, who scored them on variables

indicative of study quality. The process was done by three independent members who

subsequently reached consensus. Studies were selected for inclusion in the meta-analysis based on

the following four criteria:

“

1) The documentation of exposure in the study is sufficiently informative and clear to allow proper

comparison with other studies.

2) Internal (study-specific) conversion factors for data obtained using different measurement methods have

been used to convert concentrations expressed in particles/volume into concentrations expressed in

fibres/mL.

3) The measured data are sufficiently representative of the subjects’ occupational history.

In order to facilitate the readability of the numbers, K

values are often given as 100xK

. For KM values

is often used.

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4) Exposure measurements have been collected over a period of more than half the follow-up period.

“

Application of these criteria ruled out 14 studies, leaving 4 studies to be considered: (Gustavsson et

al., 2002; Hein et al., 2007; Peto et al., 1985; Sullivan, 2007).

There is some variability in the K

values of the 4 studies. This was by DECOS assumed to be a

consequence of differences in the quality of the exposure data, the fibre type and size distribution

of the fibres involved. A 100xK

value of 1.64 was calculated based on the 4 studies as presented in

the Table 9.

Table 9. Calculated pooled K

values (×100) for all 18 studies considered, and for the studies that

passed each successive step of the selection procedure, pooled by random effects meta-analysis

method.

The 95% CI is given between brackets (DECOS, 2010).

Next exposure concentrations corresponding to the reference environmental and workplace risk

levels for lung cancer were determined (Tables 10 and 11). No distinction was made between

chrysotile and amphiboles.

Table 10. Exposure concentrations corresponding to the reference environmental

risk levels for lung cancer. The values relate to lifetime exposure, expressed in fibres/m

, as

measured by TEM

(DECOS, 2010).

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Table 11. Workplace. Exposure concentrations corresponding to the reference workplace risk

levels for lung cancer. The values relate to occupational exposure (eight hours per day, five days

per week, for forty years), expressed in fibres/m

(with fibres/mL in brackets), as measured by

TEM

(DECOS, 2010).

This corresponds to 0.00055 fibres/mL for a risk level of 1: 100 000 and 0.0055 fibres/mL for 1:10

000.

DECOS’ meta-analysis of mesothelioma

The methodology was identical to that used for lung cancer. In the first step, 13 studies were

identified. These are presented in Table 12.

Table 12. Fibre type, production method, K

value (×10

-8

, in (fibres/mL × years

)

-1

) and SE for

each of the cohort studies considered (DECOS, 2010)

The K

values for this meta-analysis were taken from the most recent analysis by Berman and

Crump. DECOS wrote that the objections to the use of Berman and Crumps’ 33 K

values did not

apply to the K

values used in the same publication for mesothelioma, since Berman and Crump

calculated the K

value by forcing the regression line through the origin (the background mortality

for mesothelioma is virtually zero).

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When the four selection criteria described above were applied, only two studies were left as

described in Table 13 (Hein et al., 2007; Peto et al., 1985).

Table 13. Summary of all the cohort studies considered, and the studies that passed each

successive step of the selection procedure for the various types of asbestos, showing the pooled

KM values and CIs for each type of asbestos (DECOS, 2010).

Concerning Exposure concentrations corresponding to the workplace risk levels for mesothelioma

these are presented in Table 14.

Table 14. Exposure concentrations corresponding to the reference workplace risk levels for

mesothelioma.

The values relate to occupational exposure (eight hours per day, five days per

week, for forty years), expressed in fibres/m

(with fibres/mL in brackets), as measured by TEM

(DECOS, 2010).

Collective values for lung cancer and mesothelioma

DECOS then calculated values pertaining to both lung cancer and mesothelioma. These values are

presented in Table 15.

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Table 15. Exposure concentrations of various types of asbestos corresponding to the reference

risk levels of 4.10

-3

and 4.10

-5

for mesothelioma and lung cancer collectively.

The values relate to

occupational exposure (eight hours per day, five days per week, for forty years) and are expressed

in fibres/m

(with fibres/mL between brackets), as measured by TEM (DECOS, 2010).

The current working group’s conclusion on the DECOS report

It is the opinion of the current working group that the assessment method employed by DECOS is

sound. We agree on the selection of studies based on quality criteria. We assess that the report by

DECOS is a valuable contribution to the assessment of hazard levels in the current work. We

recalculated the risk levels of 4x10

-5

into 1x10

-5

by dividing the fibre concentrations in Table 15 with

a factor of five to reach the risk levels presented below in the section: “Overview

of data from different

bodies and of risk calculated by us based on animal studies”.

Our calculation on lung cancer using DECOS’ K

values

To further ensure that the estimations of DECOS are sound, we calculated the 1:10 000 risk level

for lung cancer using the K

values of DECOS and the life time risk of lung cancer in Denmark.

In Denmark, the life time risk of developing lung cancer (0 to 74 years) is 4.9% for men and 4.5%

for women. The RR caused by occupational exposure to a carcinogen, which causes cancer at

various risk levels (1:100, 1:1000 and 1:10 000) are given in Table 16.

Table 16. RR of lung cancer for carcinogens that cause 1%, 0.1% or 0.01% excess lung cancer risk

in a population with the current Danish lung cancer incidence

Men

Women

Life time risk (0-74 years)

4.9%

4.5%

2011-2015 in Denmark

Excess lung cancer risk level RR

1:100

RR= (4.9+1)/ 4.9= 1.20

RR= (4.5+1)/4.5= 1.22

1:1000

RR= (49+1)/49= 1.02

RR= (45+1)/45=1.02

1:10 000

RR= (490+1)/490= 1.002

RR= (450+1)/450= 1.002

1:100 000

RR= (4900+1)/4900= 1.000 RR= (4500+1)/4500= 1.000 2

http:/www-dep.iarc.fr/NORDCAN/DK/StatsFact.asp?cancer=180&country=208

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Thus at a risk level of 1: 10 000 the RR has to be 1.002

We use the formula for RR = 1 + K

x f x d

where

f x d

is the cumulative exposure in fibres/mL x years

Thus at a risk level of 1: 10 000 using a K

value by DECOS set only on: “Step 3. Only studies

with accurate histories”; and: “Step 4. Studies with data covering >50% of the follow-up period

(100xK

= 1.64)

RR = 1 + K

x f x d

1.002 = 1 + 0.0164 x f x d

f x d = 0.1219 fibre-years/mL

If we then divide by 40 years

We reach a mass concentration of 0.003 fibres/mL

If the calculation had been done using the K

value for all 18 studies that were considered by

DECOS and for which none were excluded based on the quality criteria of DECOS (100x K

: 0.72),

then the calculation would be as follows:

RR = 1 + K

x f x d

1.002 = 1 + 0.0072 x f x d

f x d = 0.2777 fibre-years/mL

If we then divide by 40 years

We reach a mass concentration of 0.006 fibres/mL

If the calculation had been done using the K

value for the 7 studies included in: “Step 2 only

studies that used internal conversion factors” by DECOS (100x K

: 0.91), then the calculation

would be as follows:

RR = 1 + K

x f x d

1.002 = 1 + 0.0091 x f x d

F x d = 0.2197 fibre-years/mL

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If we then divide by 40 years

We reach a mass concentration of 0.005 fibres/mL

All these three numbers, calculated by us, using either K

including a) all DECOS’ steps, b) none of

the steps, or c) only up to step 2 are in line with the risk estimates calculated by DECOS. The

current working group notes that all the risk estimates are very similar, and also very similar to the

risk estimate by DECOS (Table 11), where a risk estimate of 0.0055 fibres/mL would correspond to

a risk level of 1:10 000.

For mesothelioma, DECOS’ calculations gives0.00068 fibres/mL at a risk level of 4x10

-5

;

corresponding to 0.0017 fibres/mL at a risk level of 1: 10 000. The current working group notes that

smoking is not a risk factor for mesothelioma. The only well-established risk factor for

mesothelioma is asbestos exposure, and the current working group propose to use the risk

estimates provided by DECOS, as there is no reason to suspect that the background incidence of

mesothelioma or the ambient air levels of asbestos differ between Denmark and the Netherlands.

Afsset

Short summary of the Afsset report

In 2009, Afsset published a report with suggestions for risk levels of exposure to asbestos. Afsset is

the

French Agency for Environmental and Occupational Health Safety

under the French Agency for

Food, Environmental and Occupational Health & Safety (Afsset, 2009).

The Afsset report had the following aim: “On

7 February 2005, the Directorate General for Health

(DGS), the Directorate General for Work (DGT) and the Directorate for Economic Studies and

Environmental Evaluation requested Afsset to assess the health risks linked to short asbestos fibres (SAFs)

(length L < 5 µm, diameter d < 3 µm, with a ratio L/D≥

3). An additional mission letter addressed to the

Agency from the Directorate General for Pollution and Risk Prevention (DPPR), the DGS and the DGT,

dated 16 May 2007, requested that the field of investigation be extended to include thin asbestos fibres

(TAFs) (L ≥ 5 µm, d < 0.2 µm and L/D ≥ 3).”

Thus the report dealt with the above mentioned sizes of asbestos. In the EU, countable asbestos

fibres are defined as having a length >5 µm a diameter of less than 3 µm and a L/D

ratio of ≥3. And

thus only the

thin asbestos fibres

overlap with this definition. It was assessed by the so-called

Afsset

OEL committee

(in a collective expert appraisal) that: “The

short asbestos fibres should not to be counted

in the occupational exposure measurements. Indeed, due to the systematic presence of asbestos fibres with a

length above 5 µm in occupational activities linked to asbestos in the workplace, the OEL that will be

suggested will indirectly cover a possible health risk linked to short asbestos fibres.”

In contrast the OEL

committee stated that

“given the carcinogenic potential of thin asbestos fibres, this dimensional class is to

be included when measuring dust levels in the workplace”.

Also concerning the size Afsset in the report concludes that: “In

the current state of knowledge

establishing a dose-effect relationship for estimating the toxicity of short asbestos fibres has not been carried

out experimentally”.

Concerning thin asbestos fibres: “The

epidemiological and experimental studies

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agree in showing the existence of a carcinogenic potential of TAFs

[thin asbestos fibres].

Statistical

analyses have linked the highest probability of tumours to the classes representative of TAFs. In the current

state of knowledge, establishing a dose-effect relationship for estimating the toxicity of TAFs or a weighting

attributable to the toxicity of TAFs compared with so called "WHO" fibres has not been carried out

experimentally or validated epidemiologically”.

Affset then proceeds with the meta-analysis of cohort studies of asbestos fibres in general - TAFs

were not included in the models used by Afsset,

the Inserm model

and

The Hodgson and Darnton

model.

Afsset reached the following conclusions concerning risk levels:

“Taking

into account the current state of knowledge and the outcomes from this collective expert appraisal,

when setting the new French OEL for asbestos, Afsset recommends that the following parameters be

considered:

- the effect of asbestos fibres being cumulative and with no evidence having been found of acute toxicity when

performing a wide review of the literature, Afsset recommends the setting of the next OEL for asbestos over a

corresponding typical 8-hour working day;

- the 8-hour OEL of 10 f/l (0.01 f/mL) is currently the lowest regulatory value of many European countries.

Afsset considers that this value can constitute a relevant step in the progress towards a reduction in the risk

of asbestos exposure in France. However, for this powerful carcinogen that has no threshold, Afsset

recommends retaining a target value of 0.03 f/l, which corresponds to a level of risk of 10

-6

, according to the

retained model;

- given the carcinogenic potential of thin asbestos fibres, this dimensional class is to be included in the

measurement of dust levels in the workplace. A modification of currently used metrological techniques is

thus essential. Afsset recommends adapting the ATEM method (direct or indirect) so that it can be used as

an application in the occupational environment.

Finally, Afsset feels it is important to remember that:

- the ALARA (As Low As Reasonably Achievable) principle must be applied for a carcinogenic substance

that does not have a threshold;

- due to the fact that available data does not justify the setting of a STEL, it is recommended that the

concentration corresponding to 5 times the 8-hour OEL over a 15-minute period is not exceeded, in order to

limit the significance of exposure levels over short periods of time.“

Review of the methods and studies employed by Afsset

Concerning the discussion of different sizes of fibres the section above should be consulted.

Concerning the meta-analysis, Afsset used the so-called Inserm model with the following

explanation: “In

the report the so-called Inserm model is used (the 1997 Inserm model). The reason for this

was that:

- it has the advantage of being based on French mortality data;

- it uses simple and easy to understand hypotheses;

- the superiority of the more complex model of Hodgson and Darnton could not be demonstrated with regard

to the limitations and uncertainties associated with each of these models.

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However, the OEL committee has recalculated the potency slope factors in order to ensure that the

estimations from the Inserm model are in agreement with those of the Hodgson and Darnton model.

The application of the Inserm model, which applies to a group of exclusively male workers and a majority

exposure to a variety of chrysotile fibres (asbestos fibres considered as having the lowest carcinogenic

potential), under a continuous asbestos exposure scenario (40 hours per week and 48 weeks per year i.e.

1,920 hours per year) from the age of 20 to 65 years, thus leads to an excess risk of mortality by

mesothelioma or lung cancer compared to the French worker population of:

- 10

-4

for an exposure concentration of 3.10

-3

f /mL;

- 10

-5

for an exposure concentration of 3.10

-4

f /mL;

- 10

-6

for an exposure concentration of 3.10

-5

f /mL.

When there appears to be no quantitative evidence of acute toxicity linked to asbestos fibres, the setting of a

STEL is not recommended. In the absence of skin penetration data for asbestos fibres, the assigning of a

"skin" notation has not been retained.”

Lung cancer

Concerning lung cancer, Afsset writes they believe a linear model without cumulative exposure

threshold is the most appropriate model for calculation of lung cancer risk.

“

Inserm therefore describes the relative risk of dying from lung cancer (RRp = number of cases observed /

number of expected cases) in occupational cohorts as follows:

RRp = Observed cases/Expected cases = 1 + (Kp) x (EC) where:

EC = ∑ f x d is the cumulative exposure expressed as "f/mL

x year", i.e. the total products

resulting from exposure levels "f" (in f/mL) observed during the career history for periods "d"

(years) during which these levels prevailed.

Kp is the slope that produces the variation of the relative risk of dying from lung cancer by

additional cumulative exposure unit (1 f/mL x year). Inserm opted for practicality by

adopting a single value for the Kp risk coefficient, equivalent to + 1.0% irrespective of the

geological origin of the fibres

Equally, the extra numbers of lung cancer deaths attributable to asbestos exposure in occupational cohorts

can be expressed as follows:

Attributable extra cases = Observed cases - Expected cases = (Kp) x (EC) x (Expected cases)

“

Mesothelioma

According to Inserm, the model most suited to describing the risk of dying from mesothelioma attributable to

asbestos exposure is a linear model that depends on the level of exposure in fibres/mL based on the period of

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time that has elapsed since the exposure commenced, reduced by a 10-year period, and in which the excess

risk of an individual remains until the end of the person's life.

= K

f [(T-10)

- (T-10-d)

] if T> 10 + d

= K

f (T-10)

if 10 + d > T > 10

= 0 if T < 10

: incidence of mesothelioma

: constant (K

risk coefficient equivalent to 1.0 x 10

-8

for "chrysotile" asbestos exposure, 1.5 times higher

for combined exposures (chrysotile and amosite) and three time higher for exposure to amosite alone).

f: exposure concentration in fibres/mL

T: time elapsed since the start of the exposure, in years

d: length of exposure, in years

Inserm retained "3" as the value to represent the increase rate of the incidence of mesothelioma and the time

elapsed since the start of the exposure. Therefore, the number of mesothelioma deaths due to asbestos

exposure in a given population (Nm) is expressed as:

Nm = Im x P (Eq. 2)

[Eq. 2 is not specified in the Afsset report]”

Calculation of the lifetime risks

For the lifetime risk, the Inserm model used the all-causes mortality rates amongst the French

population.

Results

The use of these methods resulted in the following results - that also form the basis for the

conclusion given above:

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Table 17: Chrysotile concentration, expressed in terms of f-pcm/mL, associated with an

increased excess risk (designated IER by Afsset) of dying from lung cancer and/or

mesothelioma, taking into consideration a sustained exposure from the age of 20 to 65, 40 hours

a week for 48 weeks a year, in a population of exclusively male workers (Afsset, 2009).

Afsset also calculated the risks according to what they designate the Hodgson and Darnton model

- taking cumulative exposure into account

Table 18: Mesothelioma risks calculated according to the nature of the asbestos fibre

and the cumulative exposure (Afsset, 2009).

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Table 19: Lung cancer risks calculated according to the nature of the asbestos fibre

and the cumulative exposure (Afsset, 2009).

The current working group’s conclusion concerning the Afsset report

It is the opinion of the current working group that the assessment method employed by Afsset is

sound. We assess that the report by Afsset is a valuable contribution to the assessment of hazard

levels in the current work. We support the use of the INSERM model and acknowledge estimated

risk using this model: 0.003 fibres/mL corresponding to an excess risk of 1:10 000 for lung cancer

and mesothelioma combined as presented in table 17.

BAuA

The document called National Asbestos Profile for Germany from BAuA – the Federal Institute for

Occupational Safety and Health (BAuA, 2014) - had the aim to work as a starting point for

development and enforcement of national programs for the elimination of asbestos-related

diseases. In Germany, according to this document, there are two risk levels:

Acceptable Risk

and

Tolerable Risk.

In the BAuA document it is stated that:

“

Work procedures defined as low-exposure work should not exceed an exposure level of a fibre-concentration

of 10,000 fibres/m

for working without respiratory protection and medical surveillance (2018 at the latest:

1,000 fibres/m

[these correspond to 0.01 fibres/cm

, and 0.001 fibres/cm

, respectively]

The limit value

10,000 fibres/m

is called

acceptable risk level,

which is derived by a new risk concept for

carcinogenic substances developed by the Committee for Hazardous Substances (BAuA, 2013). A fibre

concentration of 10,000 fibres/m

is associated with an excess risk of lung-cancer or mesothelioma assuming

a workplace exposure for a time period of over 40 years, with 240 working days per year, and exposure

duration of 8 hours per day (Announcement 910 Asbestos, 2008). The upper limit, the

tolerable risk,

has

been set at a concentration (threshold) of

100,000 fibres/m

[this corresponds to 0.1 fibres/cm

]

(Announcement 910 Asbestos, 2008). The limit value of this additional risk is not associated with a specific

substance, but with respect to activities involving carcinogenic hazardous substances. Two risk levels are

derived defining three ranges of exposure:

Acceptable risk:

(interim limit) 4 : 10,000

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(not later than as of 2018) 4 : 100,000.

An exceedance of the limit values can only be tolerated, if the health risks associated with the exposure are

adequately controlled by means of risk management measures complying with the specifications outlined in

the catalogue of measures.

The second risk limit adopted is the

Tolerable risk:

4 : 1,000

above which a risk is intolerable. The risk refers to a working lifetime of 40 years with a continuous exposure

on every working day of 8 hours.

The

acceptable risk

defines the additional cancer risk that is accepted meaning that, statistically, 4 out of

10,000 persons exposed to the substance throughout their working life will develop cancer. The risk does not

require any additional protective measures by law, due to the low remaining occupational substance-

associated cancer risk. In contrast to that, employees should not be exposed to concentrations above the

threshold set by the tolerable risk. The two thresholds differentiating between three different concentration

ranges based on the tolerability of the magnitude of the response (cancer cases) proposed by these definitions

are in line with the ongoing national and international discussion and open up the possibility of a concept of

appropriately graduated measures (Announcement 910, 2008). The tolerable risk defines the additional

cancer risk of 4 : 1,000 that is tolerated, meaning that, statistically, 4 out of 1,000 persons exposed to the

substance throughout their working life will develop cancer. In the case of activities in the range of medium

risk (below tolerable risk, but above acceptable risk) exposure must be continuously reduced. The risk concept

lists a detailed catalogue of appropriate measures (BAuA, 2013).”

Thus this German document describes that there are two limits, the acceptable risk limit (0.001

fibres/cm

at latest from 2018), which is an acceptable risk of 4 : 100 000; and the Tolerable risk (0.1

fibres/cm

) , which corresponds to a tolerable risk of 4 : 1000.

Notably, there is in the BAuA document no description of calculations or underlying data on how

the acceptable risk limit was reached. This information was retrieved by personal contact to BAuA,

but can also be found on the internet (BAuA, 2008).

BAuA based this calculation on the following.

“According

to the US-EPA, the unit risk for lung cancer and mesothelioma is 2.3 x 10-1 per F/mL [3]

[Reference inserted by the current working group: (US EPA, 1988)].

This excess risk relates to an

exposure of 24 hours per day for 70 years and a respiratory volume of 20 m³ per day. In accordance with the

“Guide for the quantification of cancer risk figures after exposure to carcinogenic hazardous substances for

establishing limit values at the workplace” [4], this results in a specific workplace risk (40 years; 240

working days per year; 8 hours per day; respiratory volume 10 m³ / 8 hours) of 0.43 x 10-1 per F/mL. Since

the additional cancer risk is frequently expressed as a function of cumulative asbestos exposure in the form of

fibre years (fibre year = F/mL x years), the result is a workplace-specific additional

lung cancer and mesothelioma risk of 4.3% per 40 fibre years or approx. 0.1% per fibre year. The tolerable

risk of 4:1000 is therefore around 4 fibre years and the acceptable risk of 4:10000 (2018 at the latest:

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4:100000) is around 0.4 fibre years (2018 at the latest: 0.04 fibre years). Given an exposure time of 40 years,

240 working days per year and an exposure duration of 8 hours per working day, the tolerable risk works out

at a concentration of 100000 fibres/m3 and the acceptable risk at 10000 fibres/m

(2018 at the latest: 1000

fibres/m

)”.

Our conclusion concerning the BAuA report

The current working group briefly reviewed the US EPA document (US EPA, 1988), and the

Inhalation Unit Risk is indeed reported to be 2.3E-1 per (fibre/mL). The current working group

notes that the US EPA document is of an older date (1988) and is based on a range of

epidemiological studies published in the period before 1988. Notably the assessment is less

conservative as compared to the evaluations by Afsset and DECOS, but as mentioned above the

data underlying the BAuA conclusions are more than 30 years old, providing an argument that the

assessments of Afsset and DECOS are more relevant for the current assessment.

Van der Bij Study

Van der Bij

et al.

stated that existing estimated lung cancer risks per unit of asbestos exposure are

based mainly on, and applicable to, high exposure levels. Van der Bij

et al.

therefore assessed the

risk at low cumulative exposure by fitting flexible meta-regression models. The selection criteria of

relevant studies was that lung cancer risk per cumulative asbestos exposure was reported for at

least two exposure categories. From a selected 19 studies the following was extracted: 104 risk

estimates over a cumulative exposure range of 0.11 to 4,710 fibre-years/mL. Linear and natural

spline meta-regression models were fitted to the data. The authors stated that: A natural spline

allows risks to vary nonlinearly with exposure, such that estimates at low exposure are less

affected by estimates in the upper exposure categories. Associated RRs were calculated for several

low cumulative asbestos exposures. A natural spline model fitted the data best. With this model,

the relative lung cancer risks for cumulative exposure levels of 4 and 40 fibre-years/mL were

estimated to be between 1.013 and 1.027, and 1.13 and 1.30, respectively. After stratification by

fibre type, a non-significant three- to fourfold difference in RRs between chrysotile and amphibole

fibres was found for exposures below 40 fibre-years/mL. Fibre-type-specific risk estimates were

strongly influenced by a few studies. In conclusion, the natural spline regression model indicated

that at lower asbestos exposure levels, the increase in RR of lung cancer due to asbestos exposure

may be larger than expected from previous meta-analyses. The authors of that study also noted

that observed potency differences between different fibre types were lower than the generally held

consensus (van der Bij et al., 2013).

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Table 20 Data from van der Bij

et al.

in tabulated form

Model

for RR

fibre- Excess

cases Excess cases per Excess

cases

predicted

10 000

per 100 000

years/mL =

0.1 per 1000

fibres/mL over 40

lung cancer

years of work life

Natural spline 1.013

130

1300

corrected for

intercept

Natural spline 1.027

270

2700

without

intercept

The current working group notes that - based on the data from van der Bij presented in Table 20 -

risk level of 1:100 000 would be obtained at a (0.1 fibres/mL / 1300) = 0.000077 fibres/mL

when done by

linear extrapolation by us. This number is close to the risk estimates calculated by Afsset and

DECOS in 2008 and 2010.

Risk calculated based on animal studies

The current working group finds evidence in support of non-threshold mechanisms of asbestos-

induced cancer. Figure 7 gives an overview of carcinogenic animal studies described in IARC 2012.

In panel B of the figure - three studies with the lowest fibre concentration and still inducing

tumours are located to the left on the curve. Risk levels are calculated based on these three

investigations, two on chrysotile (Davis et al., 1986a, 1978) and one on amosite (McConnell et al.,

1999). The risk estimates of these studies are given in Table 25.

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Excess cancer risk in animal studies presented in IARC 2012

Davis 1985

Davis and jones 1988

Wagner 1985

Davis 1986a

Davis 1988

Davis 1986a

Davis 1978

Wagner 1980

Davis 1986b

Davis 1991a

Davis 1988

McConnell 1999, hamster

Wagner 1984b

Davis 1978 Wagner 1980

McConnell 1999, hamster

Hesterberg 1993

Davis and jones 1988

McConnel 1994

Wagner 1980

Davis 1978

McConnell 1999, Davis 1978Smith 1987

hamster 1980

Wagner Smith 1987, hamster

Muhle 1987

Davis 1986b

Excess cancer risk (%)

Chrysotile, Rats

Amosite, Hamsters

Amosite, Rats

Crocidolite, Rats

Crocidolite, Hamsters

Tremolite, Rats

Anthophyllite, Rats

100

1000

10000

100000

Fibres/mL

Excess cancer risk in animal studies presented in IARC 2012,

only data tested statistically significant in Fischer's exact test by N. Hadrup

Excess cancer risk (%)

Chrysotile, Rats

Davis 1985

Davis 1986a

Amosite, Hamsters

Amosite, Rats

Crocidolite, Rats

Crocidolite, Hamsters

Tremolite, Rats

Anthophyllite, Rats

Davis 1986a

Wagner 1980

McConnell 1999, hamster

Davis 1978

Wagner 1980

Davis 1986b

Wagner 1980

100

1000

10000

Fibres/mL

Figure 7. Excess cancer risk in animal studies presented in IARC 2012.

The cancer risk is adjusted

for the tumour incidence in the control group by use of the formula:

Excess cancer risk = ((number of

animal with tumours in treated group/total number of animals in the treated group)-(number of animals with tumours

in the control group/number of animals in the control group))/(1-( number of animals with tumours in the control

group/number of animals in the control group))*100

Panel A presents all studies regardless of whether the

number of animals in the treated group was significantly different from the control group. Panel B

presents only studies in which the number of animals with tumours was found to be statistically

different from the number of animals with tumours in the control group (Fischer’s exact test

conducted by N. Hadrup).

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As a calculation example the following is based on (Davis et al., 1986a). The OEL is derived based

on the chronic inhalation study of female mice and rats by Davis and co-workers (Davis et al.,

1986a) (Table 20). The lowest effect level for lung cancer was observed in the investigated rats,

where increased thoracic tumour incidence including mesotheliomas was found at 3.5 mg/m

/ 108

fibres/mL; the only tested dose in the study. The rats inhaled the dose for 12 months. Lung cancer

incidence (number of animals with thoracic tumours according to IARC) in chrysotile exposed rats

was 49% (21/43), while the cancer incidence in control rats was 5% (2/39).

In our assessment we include both malignant and non-malignant tumours in accordance with the

REACH guideline stating that:

“malignant tumours as well as benign tumours that are suspected of

possibly progressing to malignant tumours are taken into account in obtaining the dose-descriptor values”

(ECHA, 2012).

Table 21. Data from Davis 1986 used for calculation.

Data are given based on the presentation

provided by IARC (IARC, 2012).

Type

Mass

concen-

tration

Fibre

numbers

Animal species and

exposure

duration

and follow up period

Number of

pleural

mesothe-

liomas

number

animals

with

thoracic

tumour

the

treated

group

21 out of

animals

Number of

animals

with

thoracic

tumour in

control

group

%tumours

Chrysotile

experimental

WDC

3.5 mg/m

108

fibres/mL

Wistar rats, Exposure

period: 7h/day, 5

days per week for 12

months. Follow up

period: lifetime

2 out of 39

49%

Calculation of Excess cancer risk

This value is calculated based on the one-year chrysotile inhalation study in rats by (Davis et al.,

1986a) (values summarised in Table 21):

Excess cancer risk:

Observed excess cancer incidence at 108 fibres/mL:

Formula used:

Observed excess cancer incidence = ((treated animals with thoracic tumours/total treated animals)-

(control animals with thoracic tumours/total control animals)) / (1-(control animals with thoracic

tumours/total control animals)

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And with the numbers from Table 21 inserted into the formula:

Observed excess cancer incidence = (21/43- 2/39) / (1-2/39) = 0.46 = 46 %

Correction of dose metric for humans during occupational exposure (8 h/day):

108 fibres/mL x (7 h/day) / (8 h/day) x (6.7 m

/10 m

) = 63.3 fibres/mL

The risk at 1% is then calculated by

63.3 fibres/mL / 46% = 1.4 Fibres/mL

Calculation of dose levels corresponding to risk level of 10

-5

(1: 100 000), 10

-4

(1: 10 000) and 10

-3

(1:

1 000) - under the assumption of linear extrapolation.

Table 22. Calculated excess thoracic tumour incidence at different chrysotile fibre

concentrations (8h-TWA)

Excess lung cancer incidence Chrysotile Air

concentration

1: 1 000

0.14 fibres/mL

1: 10 000

0.014 fibres/mL

1: 100 000

0.0014 fibres/mL

Considerations on the potential differences in potencies among the asbestos

types.

Concerning animal studies, as can be seen on Figure 4 illustrating the NOAEC and LOAEC values

of non-carcinogenic endpoints, it is not possible to assess that one type is more potent than the

other. Looking at fibre concentrations of lung tumour induction as illustrated in Figure 6, there is

some indication that, concerning thoracic tumours, the serpentine asbestos chrysotile is more

potent than the amphibole asbestos amosite.

IARC in 2012 reported that there was evidence from epidemiological studies that exposure to

the serpentine asbestos, chrysotile, is less potent in the development of these cancers, in particular

for mesothelioma, as compared to the amphibole asbestos types. There IARC also reported that

there however was a debate on whether this was the case for lung cancer (IARC, 2012). More

details of this debate are given in section 7.7.1. DECOS wrote that – for mesothelioma – a clear

difference in carcinogenic potential was discernible between chrysotile asbestos and the

amphiboles, which is why DECOS has two different risk estimates for chrysotile and for

amphiboles. As presented in Table 23, the excess cancer risk differs by a factor of 5 for lung cancer

and mesothelioma combined, with amphiboles being the most potent. Finally Afsset concluded

that: ”All

known and commercialised mineral varieties of asbestos are likely to cause cancer in humans by

inhalation. A single value will be recommended to protect from the effects of all mineral varieties”

(Afsset,

2009). Afsset thus did not distinguish between the different asbestos types.

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Notably, the various asbestos types are in virtually all cases cross-contaminated with each other

suggesting that it is difficult to pinpoint that Danish workers would only be exposed to single

types.

Overall, it is the assessment of the current working group that it cannot be excluded that

amphiboles are more potent carcinogens than the serpentine asbestos, chrysotile; on the other

hand, occupational exposure to asbestos will likely include mixed exposures and the current

working group therefore recommends to use the estimates by DECOS on amphiboles for the

setting of a health-based OEL.

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Overview of data from different bodies - and of risk calculated by the current working group based on

animal studies

The exposure levels

leading to excess cancer risk

by different bodies and articles are given in Table 23.

Table 23 Overview of

exposure levels (8h-TWA) leading to excess cancer risk

by different bodies

Risk estimates taken from reports and articles

Excess cancer

incidence

(specified

whether lung

cancer and/or

mesothelioma)

Meta-analysis

Human

studies

For

lung

cancer

(DECOS,

2010)

Meta-analysis

Human

studies

For

mesothelioma

(DECOS,

2010)

Meta-analysis

Human

studies

For

mesothelioma

(DECOS,

2010)

Meta-analysis

Human

studies

For

mesothelioma

and

lung

cancer

combined

(DECOS,

2010)

Meta-analysis

Human

studies

For

mesothelioma

and

lung

cancer

combined

(DECOS,

2010)

Meta-

analysis of

Human

studies

Lung

cancer

(Afsset,

2009)

Meta-analysis

Human

studies

mesothelioma

(Afsset, 2009)

Meta-analysis

Human

studies

Lung cancer

and

mesothelioma

(Afsset, 2009)

Meta-analysis of Human

studies (BAuA)

BAuA based their risk

levels on the US EPA

unit risk for the general

public

for lung cancer

and mesothelioma

(2.3 x

10-1) per fibre/mL. And

converted

this

0.43x10

-1

per fibre/mL

for the working life.

And found a risk of 0.1

% per fibre year.

Asbestos

Designated

“asbestos”

type:

Calculations

based on Van

der Bij (van der

Bij et al., 2013)

based on

lung

cancer.

1:1000

1:10 000

1:100 000

Asbestos type:

Concerning

lung cancer, no

distinction was

made between

chrysotile and

amphiboles

0.055

fibres/mL

0.0055

fibres/mL

0.00055

fibres/mL

Asbestos type:

Chrysotile

Asbestos type:

Amphiboles

Asbestos type:

Chrysotile

Asbestos type:

Amphiboles

Asbestos

type:

Chrysotile

Asbestos type:

Chrysotile

Asbestos type:

Chrysotile

0.7 fibres/mL

0.07

fibres/mL

0.007

fibres/mL

0.017

fibres/mL

0.0017

fibres/mL

0.00017

fibres/mL

0.05 fibres/mL

0.005

fibres/mL

0.0005

fibres/mL

0.01 fibres/mL

0.001

fibres/mL

0.0001

fibres/mL

0.047

fibres/mL

0.0047

fibres/mL

0.00047

fibres/mL

0.1 fibres/mL

0.01

fibres/mL

0.001

fibres/mL

0.03

fibres/mL

0.003

fibres/mL

0.0003

fibres/mL

1 fibre/mL

0.1 fibres/mL

0.01 fibres/mL

Asbestos type:

Based

studies

chrysotile,

amphiboles,

and so-called

mixed

0.0077

fibres/mL

0.00077

fibres/mL

0.000077

fibres/mL

The recommendation from Afsset is given as f-pcm/mL: an abbreviation for fibres-measured by phase contrast microscopy/mL.

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The current working group ensured the calculations of DECOS by re-calculating the risk levels for lung cancer using values for lung

cancer risk in Denmark (Table 24). The estimates by the current working group, detailed in the table, based on DECOS, are in line with

those calculated by DECOS itself. The DECOS value on the risk level for lung cancer – when no distinction was made between chrysotile

and amphiboles – was 0.00055 fibres/mL (risk level 1: 100 000) (Table 24). Smoking is not a risk factor for mesothelioma. Therefore, the

current working group is of the opinion that the risk assessment for asbestos-induced mesothelioma based on epidemiological data by

DECOS is also valid for Denmark.

Table 24

Exposure levels leading to excess cancer risk

calculations by the current working group based on Danish numbers for lung

cancer risk and DECOS’ K

values.

For comparison DECOS’ own calculation is inserted in the last column.

Risk estimates calculated by us (NFA) based on the DECOS report

Excess

cancer

incidence

Calculations by the current working group based on

a K

value for lung cancer set by DECOS based on

quality Criteria “Step 3. Only studies with accurate

histories”; and “Step 4. Studies with data covering

>50% of the follow-up period (100xKL = 1.64).

Calculations by the current working group using the

value for all 18 studies that were considered by

DECOS and for which none were excluded based on

the quality criteria of DECOS (100x K

: 0.72).

Calculations by the current working group

using the K

value for the 7 studies fulfilling

DECOS’ Step 2 only studies that used

internal conversion factors

(100x K

: 0.91),)

Asbestos type: Concerning lung cancer, no

distinction was made between chrysotile and

amphiboles.

1:1000

1:10 000

1:100 000

0.03 fibres/mL

0.003 fibres/mL

0.0003 fibres/mL

Asbestos type: Concerning lung cancer, no distinction

was made between chrysotile and amphiboles.

Asbestos type: Concerning lung cancer, no

distinction was made between chrysotile and

amphiboles.

0.05 fibres/mL

0.005 fibres/mL

0.0005 fibres/mL

Asbestos type: Concerning

lung cancer, no distinction

was made between chrysotile

and amphiboles.

0.055 fibres/mL

0.0055 fibres/mL

0.00055 fibres/mL

DECOS’ own result

Meta-analysis of

studies

For lung cancer

(DECOS, 2010)

Human

0.06 fibres/mL

0.006 fibres/mL

0.0006 fibres/mL

Concerning animal data, the current working group regards the risk levels calculated based on animal studies (Table 25) as being less

conservative – compared to the risk estimates based on epidemiological data. The current working group recommends to use

epidemiological data for setting the health based OEL.

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Table 25 Risk estimates by the current working group based on animal studies

Excess cancer

incidence

(specified

whether lung

cancer and/or

mesothelioma)

Chrysotile

Rat inhalation

study of 3.5

mg/m

/ 108

fibres/mL

(L>5 µm)

Method II

ECHA**

(Davis et al.,

1986a)

used

Chrysotile

Rat inhalation study of 2 mg/m

/ 390

fibres/mL (L>5 µm)

Method II

ECHA**

(Davis et al., 1978), used to calculate

fibres/mL at 1% risk

At 1% = 10.7 fibres/mL

Amosite,

Hamster inhalation study of 3.7

mg/m

/ 165 fibres/cm

(L>5 µm, and 38 of

these were longer than 20 µm/cm

) Method II

ECHA**

(McConnell et al., 1999), used to calculate

fibres/mL at 1% risk

At 1% risk = 3.2 fibres/mL

to calculate

fibres/mL at

1% risk

At 1% = 1.4

fibres/mL

1:1000

1:10 000

1:100 000

0.14 fibres/mL

0.014 fibres/mL

0.0014 fibres/mL

1.07 fibres/mL

0.107 fibres/mL

0.0107 fibres/mL

0.32 fibres/mL

0.032 fibres/mL

0.0032 fibres/mL

The animal studies selected were the two with the lowest chrysotile fibres/mL and the one with the lowest amosite while still increasing neoplasms in

rats/hamsters. There were studies described by IARC who did not report fibre numbers, but none of these had a mass concentration below the studies

included in this table.

Based on the considerations above, the current working group recommends that DECOS’ values are used for hazard assessment and

suggest using the most conservative value for amphiboles, for lung cancer and mesothelioma combined. The value is: 0.0001 fibres/mL,

corresponding to a risk level of 1: 100 000 (Table 26).

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Table 26 Recommendation by the current working group on:

exposure levels (8-h- TWA) leading to excess cancer risk

Excess cancer incidence Risk levels (8h-TWA) based on a meta-analysis

of lung cancer or

conducted by DECOS on Human studies of

mesothelioma and lung cancer combined – calculated

mesothelioma

based on exposure to amphibole asbestos

1:1000

0.01 fibres/mL

1:10 000

0.001 fibres/mL

1:100 000

0.0001 fibres/mL

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Summary and conclusion

The two risk assessments by DECOS (2010) and Afsset (2008) lead to practically identical risk

estimates for excess human lung cancer risk mortality – in relation to asbestos exposure. Taking

both assessments together, a mean 8h-TWA asbestos exposure over 40 working years of about

0.0001 fibres/mL would lead to an excess mesothelioma and lung cancer mortality rate of 1 x 10

-5

Our calculations using Danish numbers for asbestos-induced lung cancer and based on the K

value for lung cancer set by DECOS based on a) DECOS’ own quality criteria; and b) DECOS’ K

value for their initially selected 18 studies – were all in line with the number on lung cancer given

by DECOS itself, suggesting that the risk estimates are quite robust. Notably, risk estimates based

on animal data did not indicate that animal studies would provide a lower risk estimate for lung

cancer. The current working group recommends using human data in setting risk levels for a

health-based OEL.

The current working group suggests that the following

exposure levels leading to excess cancer risk

are

used:

Excess cancer incidence

of lung cancer or

mesothelioma

1:1000

1:10 000

1:100 000

Risk levels (8h-TWA) based on a meta-analysis

conducted by DECOS on Human studies of

mesothelioma and lung cancer combined – calculated

based on exposure to amphibole asbestos

0.01 fibres/mL

0.001 fibres/mL

0.0001 fibres/mL

7.8. Reproductive toxicity

7.8.1. Human data

It is clear that if asbestos has a genotoxic effect the risk of teratogenicity exists. A key question,

however, is whether there is translocation of asbestos fibres to the germ cells, or to the foetus. The

tissues and placentas of autopsied stillborn infants were investigated for the presence of asbestos

fibres. Asbestos fibres were detected in 50% of the foetal digests and 23% of the placental digests of

82 stillborn infants. Various asbestos types were present: 88% were chrysotile, 10% were tremolite,

and 2% were actinolite and anthophyllite. The organs in which the fibres were most frequently

present were: Lungs (50%), muscle (37%), placenta (23%), and liver (23%). However, the number of

fibres were highest in the liver (58 736 fibres/g), placenta (52 894 fibres/g), lungs (39 341 fibres/g),

and in skeletal muscle (31 733 fibres/g). Concerning placentas from liveborn foetuses asbestos

fibres were detected in 15% of these, but only in small numbers. In placentas of the stillborn the

fibre count was 52 894 fibres/g whereas in liveborn foetuses it was only 19 fibres/g. The fibre

presence in the stillborn foetuses was associated with the history of previous abortions and with

placental diseases (Haque et al., 1998). In a study by the same group in 1996 similar results were

obtained studying 40 stillborn infants and placental digests of 45 liveborn infants (Haque et al.,

1996), and similar data were reported by the same group in 1992 (Haque et al., 1992).

A group of women and girls exposed to crocidolite at Wittenoom consisted of 2968

individuals and included 3 cases of choriocarcinoma and 3 cases of hydatidiform mole. In 4 of

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these cases the females had lived with asbestos company workers who brought their dusty work-

clothes home for washing (Reid et al., 2009).

Talc is chemically related to asbestos. The association between genital exposure to talc and the

occurrence of ovarian cancers was assessed in in 215 females having this cancer form. A control

population of 215 women was matched by age, race, and residence. Ninety-two (42.8%) of the

women with cancer regularly used talc either as a dusting powder. This was used on the perineum

or on sanitary napkins. The number in the control group was 61 (28.4%). This gave an RR of 1.92

having a P-value of less than 0.003 for ovarian cancer. Women who had had regularly engaged in

both practices had an RR of 3.28 P-value of less than 0.001 as compared to women who had done

neither of the practices. The authors of that article suggest that “this provides some support for an

association between talc and ovarian cancer” (Cramer et al., 1982).

A literature review of mesothelioma in children, suggested that mesothelioma has a relatively

short latency period in children (Wassermann et al., 1980).

7.8.2. Animal data

Having reviewed the inhalation toxicity data of asbestos in animal models, we found no

reproductive effects to be reported in these. However from a gavage study there is data concerning

the trans-placental transfer of asbestos in pregnant mice. Pregnant mice were orally administered

chrysotile asbestos by gavage. The mice were given two doses of 50 µg chrysotile. After mating 2

days later, the mice received two additional doses. The lungs and liver of pups were found to

contain chrysotile fibres at 780 fibres/g lung and 214 fibres/g liver. Weight gain and mortality was

not different from that of pups in a control group (Haque et al., 2001). This aspect was also

investigated in a previous study from the same group (Haque and Vrazel, 1998). Teratogenicity

was investigated in mice receiving crocidolite, chrysotile, or amosite at 40 mg/kg bw by

intraperitoneal injection. In comparison with a control group, the percentage of live foetuses was

increased after crocidolite, whereas the number of dams with early dead foetuses was increased in

the chrysotile and amosite groups. The incidence of external malformations (mainly reduction

deformity of limb) was increased in the amosite group. And the incidences of skeletal

malformation (mainly fusion of vertebrae) were increased in all three asbestos groups (Fujitani et

al., 2014).

Collectively the data on animal studies suggest the transfer of asbestos from mother to

foetus and suggest a potential for teratogenicity at an intraperitoneal dose of 40 mg/kg bw in mice.

7.8.3. In vitro data

No relevant in vitro data were identified.

7.9. Mode of action considerations

The mutagenic/genotoxic mode of action of asbestos likely involves at least two modes of action a)

frustrated phagocytosis – the inability of macrophages to fully engulf long fibres leading to chronic

inflammation and oxidative stress; and b) the genotoxic effects of iron – iron is a pronounced

constituent of some asbestos types. Also pertaining to the size and rigidity of the asbestos fibres is

c) the hypothesis of a needle-like mode of action in the mammalian tissues potentially causing the

widespread distribution of asbestos fibres in various tissues and potentially interfering with

chromosome alignment during cell division.

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7.10. Lack of specific scientific information

The toxicology of asbestos in general has been well investigated, although notably some types of

asbestos have been investigated more than others. In general for all types, it is noted that the

literature on sensitisation and asbestos is lacking.

8. Groups at extra risk

It has been reported that there is interaction between the exposure to asbestos and to tobacco

smoke in relation to the induction of lung cancer (Markowitz et al., 2013; Ngamwong et al., 2015;

Selikoff et al., 1968). Mesothelioma has been reported to develop in children with a faster onset as

compared to adults; and also the maternal transfer of asbestos to the foetus raises concern (Haque

et al., 1996, 1992).

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