The role of expert judgement and conceptual …Basel, 1_9_2016 6 MEDICHEM 2016 Andrea Hartwig: OEL...

Basel, 1_9_2016 1

MEDICHEM 2016 Andrea Hartwig: OEL setting by the MAK commission: Expert judgement and conceptual approaches

DFG MAK

KIT – Universität des Landes Baden-Württemberg und

nationales Forschungszentrum in der Helmholtz-Gemeinschaft

Institut für Angewandte Biowissenschaften, Lebensmittelchemie und Toxikologie

www.kit.edu

DFG MAK

The role of expert judgement and conceptual

approaches in setting OELs

by the German MAK commission

DFG Senate Commission for the Investigation

of Health Hazards of Chemical Compounds in

the Work Area (MAK Commission)

Chair: Prof. Dr. Andrea Hartwig,

Karlsruhe Institute of Technology (KIT)

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DFG MAK

• Evaluation of chemical substances at

the workplace

(single substances)

• Conceptional work

(criteria for risk assessment)

Tasks of the MAK Commission

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DFG MAK MAK and BAT values….

• derived by the „DFG Commission for the Investigation of Health

Hazards of Chemical Compounds in the Work Area“ (MAK

Commission)

• published anually in the List of MAK and BAT values and documented

in the „Toxikologisch-arbeitsmedizinische Begründungen“, available

also in an English translation

• Prior to final publication: 6 months time for scientific comments

• based on scientific evidence, not technical or economic considerations

Since 2012:

All lists and documentations available in „open access“ at Wiley VCH:

http://onlinelibrary.wiley.com/book/10.1002/3527600418

... as well as original publications to selected aspects in international

peer reviewed scientific journals ...

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DFG MAK Structure of the MAK commission

Currently 35 members, permanent guests, guests and ad

hoc experts, covering the fields of

Epidemiology

Occupational medicine

Toxicology

Pathology

Analytical chemistry

Related disciplines

Scientific secretariat

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DFG MAK Working groups

Skin and allergy (Schnuch)

Evaluation of components of metal-

working fluids, hydraulic fluids and

lubricants (Fatasch)

Establishment of threshold values for

dusts (Hallier)

Establishment of threshold values in biological material

(Drexler)

Air analyses (Hebisch)

Analyses in biological material

(Göen)

Establishment of MAK values

(Hartwig)

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DFG MAK Ad hoc working groups

Classification of carcinogens

(Greim)

Percutaneous absorption

(Bader)

Carcinogenicity of biopersistent

granular dusts (Greim)

MAK values and prenatal toxicity (Greim, Schriever-

Schwemmer)

Heavy metals (Hartwig)

Nanoparticles (Hartwig)

Genotoxic carcinogens (with SKLM)

(Hartwig)

Exposure limits for local effects (with AGS) (Brüning)

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DFG MAK Hazard identification vs. risk assessment

Acute toxicity (inhalative,

dermal, oral)

Irritation (skin, eye)

Subacute, chronic toxicity

Sensibilisation (skin, respiritory

tract)

Toxicokinetic

Genotoxicity, Mutagenicity

Carcinogenicity

Reproductive toxicity

„Hazard identification“ „Risk assessment“

Dose-response relationships

NOEL, NOAEL

Reversibility

„Mode(s) of action“

Derivation of threshold

values if possible

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DFG MAK

• Data collection

• Published literature with respect to

• epidemiological data,

• occupational medical reports,

• toxicological properties

• other relevant information

• Data evaluation

• relevance for current assessment

• validity of the studies (e.g., according to OECD guidelines if

possible, otherwise expert judgement)

• Company reports, if full study report available, handled

confidentially

Derivation of MAK values: Data base

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DFG MAK

• Identification of the most sensitive parameter related to the exposure

of a given substance, taking into account

• local effects (mucous membranes of respiratory tract and eyes)

• systemic effects

• Identification of a „no observed adverse effect level“ (NOAEL) for the

most sensitive and relevant parameter for substances without genotoxic/

carcinogenic properties

• Decision on „adversity“ by expert judgement

Derivation of MAK values: General approach

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DFG MAK

Derivation of MAK values for substances

without genotoxic/carcinogenic properties

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DFG MAK

• Occupational medical and epidemiological studies

• Preferentially longitudinal studies with repeated determination

and documentation of past and present external and internal

exposure

• Human volunteer studies

• Exposed under controlled conditions

• Establishment of NOAEL and dose-effect relationship

In case of good quality data MAK value is established at

level of NOAEL after correction for higher breathing volume

at work places in case of systemic effects; consideration of

longer daily exposure at work places if not indicated otherwise

by toxicokinetic data (preferred value approach)

Derivation of MAK values: Effects in humans

In case of good quality data MAK value is established at level

of NOAEL (preferred value approach: 1,2,5 ppm or mg/m³ etc.)

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DFG MAK

• Minimum requirements:

• Valid 90-day inhalation study for assessment of local and

systemic effects, or

• Establishment of NOAEL

Assessment of potential differences in sensitivity of humans,

considering especially toxicokinetic and toxicodynamic data

• Valid 90-day study with oral application for assessment of

systemic effects, accompanied by information about the local

effects of a substance, especially on the respiratory tract

If not suggested otherwise by these data, MAK value is

established at level of half the extrapolated NOAEL, after

consideration of species-specific toxicokinetic correction

factors (preferred value approach)

Derivation of MAK values: Effects in animals

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DFG MAK

• if critical effect is irritation (e.g., SAR, Draize-test, pH-value);

usually no time-extrapolation required unless structure-activity-

relationship to other compounds indicate the time-dependence of

irritation

• if critical effect is systemic and SAR data are available

In some cases, the MAK value is derived from the NOAEL of a 28-

day study:

otherwise no MAK-value II b


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DFG MAK

If no NOAEL, but dose-response curve for critical effect available:

•Expert judgement

- severity of effect

- steepness of dose-response-curve

•Benchmark-dose calculation if data suitable

otherwise no MAK-value II b


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DFG MAK Other relevant aspects….

• Pregnancy groups

• Biological Tolerance (BAT), exposure equivalents established

for carcinogenic substances (EKA) and BLW values

established in case of insufficient data for setting a BAT value

• Sensitizing effects (skin, respiratory tract) “Sa, Sh, Sah“

• Danger of percutaneous absorption „H“

• Consideration of surveillance of respective exposure and

development of methods for analyses in air and biological

materials

• Germ cell mutagenicity

• Limitation of exposure peaks

• Carcinogenicity

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DFG MAK

Values in biological media

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DFG MAK

Definition

• Concentration of a chemical substance, its metabolites or an effect

indicator

o in appropriate biological material

o at which the health of an employee is usually not affected (even after

repeated or long-term exposure)

BAT values are based on a

• relationship between external and

o internal exposure or

o the effect of the substance

BAT values

BAT value exceeded:

• average concentration, in one person, after several

investigations BAT values are not established for carcinogenic substances!

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DFG MAK

EKA (Expositionsäquivalente für

krebserzeugende Arbeitsstoffe; exposure equivalents for

carcinogenic substances)

BLW (Biologischer Leitwert; biological guidance value)

BAR (Biologischer Arbeitsstoff-Referenzwert; biological

reference value)

Biological values for carcinogens

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DFG MAK Future challenges

for setting occupational exposure levels

Establishment of health-based exposure limits also for carcinogenic

substances

Consideration of modes of action and conceptional work required

Consideration also of non-cancer effects of the respective substance

Due to more detailed knowledge inclusion of more sensitive

endpoints, for example subtle neurotoxic effects

Frequently very complex data, which require very detailed evaluation of

the adversity of the effects

Evaluations and classifications of groups of substances (e.g.,

Granular Biopersistent Dust (GBS), nanomaterials, metal ompounds)

Conceptional work required

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DFG MAK

Carcinogenic substances

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DFG MAK

Hazard identification vs. risk estimation

Health based exposure limits for carcinogens at workplaces

also required by the german legislation

(„Gefahrstoffverordnung“)

Important question:

• Is there a carcinogenic potential relevant under realistic exposure conditions?

• What are the underlying mechanisms involved?

• Is it possible to define threshold values which protect from carcinogenicity?

Genotoxic/ carcinogenic substances: Background

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DFG MAK

Tumor incidence

Dose

Measured

values

LOEL

Extrapolation

„Black Box“

? ?

?

?

The problem of dose-response-relationships

in case of carcinogenic compounds…

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DFG MAK

Dose

LOEL

Extrapolation

„Black Box“

? ?

?

?



Measured

values

Tumor incidence

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DFG MAK

Dose

LOEL

Extrapolation

„Black Box“

? ?

?

?



Measured

values

Tumor incidence

Current approach for

genotoxic carcinogens

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DFG MAK Past and current approaches for workplace carcinogens

TRK-Values (technical guidance concentration)

• Exposure-Risk-Relationships (Expositions-Risiko-Beziehungen; ERB)

established by Ausschuss für Gefahrstoffe (AGS):

• Tolerated or accepted risks:

• 4:1,000 (tolerated risk); 4:10,000 (accepted risk 2013); 4:100,000;

accepted risk 2018 at the latest)

• MAK categories 4 and 5

(since 1998; similar approach by SCOEL since 2008)

Since 2005: Requirement for setting health-based exposure

limits also for carcinogens

Strictly based on technological considerations; valid until 2005

In Germany two different approaches:

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DFG MAK MAK categories for genotoxic/ carcinogenic

substances

1. Substances that cause cancer in humans and can be assumed to

contribute to cancer risk (adaquate epidemiological evidence or

limited epidemiological evidence and mode of action relevant to

humans)

No MAK or BAT value established

2. Substances that are considered to be carcinogenic in humans

based on sufficient data from long-term animal studies or limited

evidence from animal studies, substantiated by evidence from

epidemiological studies and/or supported by mode of action (in

vitro tests, short-term animal studies)

No MAK or BAT value established

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DFG MAK

3. Substances that cause concern that they could be carcinogenic to

humans but cannot be assessed conclusively because of lack of

data. The classification in Category 3 is provisional.

a. Substances for which the criteria for classification in category 4 or 5

are fulfilled but for which the database is insufficient for the

establishment of a MAK or BAT value.

b. Substances for which in vitro or animal studies have yielded

evidence of carcinogenic effects, but not sufficient for

classification of the substance in one of the other categories

(further studies are required). A MAK or BAT value can be

established in the absence of genotoxicity.

MAK categories for genotoxic/ carcinogenic

substances

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DFG MAK

4. Substances that cause cancer in humans or animals ... and for which

a MAK value can be derived. A non-genotoxic mode of action is of

prime importance; no contribution to human cancer risk is

expected at exposure observing MAK and BAT values (mode of

action well understood, related for example to increases in cellular

proliferation, inhibition of apoptosis or disturbances in cellular

differentiation)


substances

Example:

• Granular biopersistant dust (GBD or GBS)

(inert dust without additional specific toxicity)

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DFG MAK Granular biopersistent particles (GBP)

• Lung as critical target organ upon inhalation

• Carcinogenic in experimental animals on high-exposure

conditions (particle overload)

• Proposed mechanism: chronic inflammation, macrophage

activation, secondary genotoxicity

NOAEL and thus MAK/OEL should protect from chronic

inflammation

MAK carcinogenicity category 4

MAK value (respirable fraction): 0,3 mg/m³ (density 1 mg/cm3)

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DFG MAK

5. Substances that cause cancer in humans or animals ... and for

which a MAK value can be derived. A genotoxic mode of action is

of prime importance but is considered to contribute only very

slightly to human cancer risk, provided the MAK and BAT values

are observed (must be supported by information on the mode of

action, dose-dependence and toxicokinetic data pertinent to species

comparison)


substances

Up to now only five substances listed:

• Acetaldehyde

• Ethanol

• Isoprene

• Styrene

• Dichloromethane (new)

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DFG MAK

Metabolism of styrene and

styrene-7,8-oxide

Example Styrene (MAK Category 5)

DNA adducts

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DFG MAK

• Critical metabolite formed by mouse, rat and man

• Extent assessed by biochemical marker Hb-adducts:

Mouse 1 Rat 1/2 - 1/3 Man 1/20 - 1/50

Metabolism of styrene and styrene-7,8-oxide

• Carcinogenic risk calculation for systemic styrene exposure

• Based on the positive oral studies in mice (lung tumors) and one

positive oral study with styrene oxide in rats

• Exposure at the workplace (40 years, 8 hrs per day, 5 days per week,

48 weeks per year) at

20 ppm results in an estimated risk of about 1 : 20 000,

which is well below the risk of endogeneous epoxides

(for example, ethylene oxide)

Category 5, MAK 20 ppm

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DFG MAK Example Ethanol (MAK Category 5)

• Human carcinogen; critical metabolite acetaldehyde

• Concentration of ethanol in blood over time determines the

internal body burden of the critical metabolite acetaldehyde

• Humans are physiologically exposed to ethanol due to endogenous

ethanol production

→ amount and range of internal life-time body burden are

known

→ correlation of external ethanol concentration with ethanol

concentration in blood is also known

→ at an exposure of 500 ml ethanol/m3 during the entire working

life, the average life-time body burden of ethanol is still within

the range of variation of the endogenous body burden

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DFG MAK

From: Seitz and Stickel, Genes Nutr (2010) 5: 121 - 128

Example Ethanol (MAK Category 5)

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DFG MAK Life-time body burden of ethanol without and with occupational exposure

→ workplace exposure to concentrations up to 500 ml/m3 would contribute

only little to cancer risk

0

25

50

0 500 1000

Ethanol concentration at the workplace [ml/m 3 ]

Lif

e-t

ime

bo

dy b

urd

en

[mg

/L *

ye

ars

]

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DFG MAK Current discussion

Science-based threshold values also for genotoxic carcinogens?

• Must be evaluated on a case-by-case basis

• Required information:

• All types of DNA lesions induced

• Dose-response-relationship in the low dose range for DNA

lesions

• Cellular consequences of respective DNA lesions

• Endogenous „background“ frequency of the same or similar

genotoxic compound or metabolite and/or DNA lesions

• Toxicokinetic data/Modelling

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DFG MAK Current status

• New analytical methods enable measurement of some DNA adducts

also as background frequencies and in the low dose range

• Frequently linear increase of DNA adducts with dose within the

low dose range

• However, in some cases increase in mutation frequencies non-

linear dose-response curve

Significance of DNA adducts for mutagenicity and carcinogenicity?

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DFG MAK

Working group on „Genotoxic carcinogens“ (MAK/SKLM)

Aim:

• development of concepts for integrating the manifold

mechanisms of carcinogenicity including current

knowledge of cell biology into risk assessment and

classification of carcinogens

Currently

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DFG MAK Risk assessment of nanomaterials......

published in

2013

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DFG MAK Distinction of nanomaterials

for toxicological risk assessment

Granular biopersistant particles (GBP) with no or little additional

chemical toxicity („inert“ particles)

Coated nanoparticles, e.g. „quantum dots“

Toxic or potentially toxic metal-based nanoparticles

Fibre-like nanomaterials, e.g. nanotubes

Nanoparticles as delivery systems, e.g. drug delivery

Grouping of nanomaterials to establish general approaches

for risk assessment:

…

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DFG MAK

GBP microscale

• Quantitative or qualitative differences in toxicity and mode of action?

• Differences in uptake/passage through biological membranes?

• Differences in toxicokinetics?

• Differences in receptor interactions?

• Additional target organs other than lung (cardiovascular system, brain)?

• Chronic inflammation most sensitive parameter? Critical effect also for

carcinogenicity?

• Differences in genotoxicity (direct vs. indirect genotoxicity)?

• In case of primarily quantitative differences, which parameters are

decisive for setting OELs (e.g., mass, surface area/reactivity, single

particles, aggregates)?

GBP nanoscale

Microscale vs. nanoscale

granular biopersistent particles (GBP)

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DFG MAK Summary and conclusions

• Evaluation of chemical substances at the workplace

• MAK and BAT values derived by expert judgement

• Extrapolation factors based on toxicokinetic considerations and

data quality

• Conceptional work

• Increasing significance with respect to

• More subtle toxicological relevant effects

• Groups of substances (e.g., particles, metals)

• Chemical carcinogens

• Identification of research needs

Basel, 1_9_2016 43


DFG MAK Thanks to

• all members, guests and ad hoc experts of the

MAK commission

• the scientific secreteriat of the MAK commission

• the DFG for financial and other support

The role of expert judgement and conceptual …Basel, 1_9_2016 6 MEDICHEM 2016 Andrea Hartwig: OEL...

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