04 heederik benzeno

Standard setting in the Netherlands: approaches and examples

Prof Dick Heederik, PhDInstitute for Risk Assessment Sciences, Division of Environmental

EpidemiologyUtrecht University, The Netherlands

[email protected]

mailto:[email protected]

http://www.gezondheidsraad.nl/nl

Standard setting in the Netherlands

1. Health Council, independent, protected by law: proposal for a standard

2. Socio Economic Council (tri-partite): feasibility of the standard

3. Ministry of Social Affairs and Employment: sets the standard

4. Procedures described in guidelines of health council

Standard may be lower than an European Limit (Scientific Committee Occupational Exposure Limits (SCOEL)


Standard setting in the Netherlands

1. Committee consists of toxicologists, epidemiologists, hygienists

1. General trend is that epidemiological information (human studies) is becoming more and more important

2. Regular collaboration with other organizations (Nordic Expert Group)

1. Literature evaluation by a combined subgroup2. Hazard evaluation per country


Standard setting in the Netherlands: carcinogens1. Non-genotoxic carcinogens (threshold)2. Genotoxic carcinogens with a non-stochastic mechanism

(threshold)HEALTH BASED RECOMMENDED OCCUPATIONAL EXPOSURE LIMIT

3. Genotoxic carcinogens with a stochastic mechanism (no threshold)

4. Genetoxic carcinogens with an unknown mechanism (assume no threshold)

Often linear E-R, more often data drivenRISK CALCULATIONS exposure at on average 10-4 and 10-6 extra risk per year (4.10-3 and 4.10-5 per 40 years exposure)

Differences with other organizations

1. EU REACH regulatory framework: 1. DMEL comparable with a risk calculation on the

basis of a linear model2. Large assessment approach (based on margin of

exposure principle as applied by European Food Safety Agency), not relevant for occupational standards

2. SCOEL linear models, no guidance document

Steps in the risk assessment proces

- Selection of information useful to derive an HBROEL or risk figures (complete review)

- Selection of critical study/studies: Quality review/pooled-analysis/meta-analysis

- Estimation of carcinogenic activity of an agent (exposure-response)

- Calculation of risk in relation to exposure/derivation of a NOAEL or nowadays a BMD(L)

- Obtaining exposure level at which a certain absolute risk is realized or Health Based Occupational Exposure Limit (HBROEL)

Exposure assessment and evidence based medicine✽ Recent Dutch Health Council

report 2009

✽ App. 200 papers identified

✽ 50% major quality problems, exposure assessment component, underpowered, measurement endpoint, design

✽ These studies were not considered in the evaluation

Stepwise exclusion of studies with quality issues (Lenters et al., EHP 2011, AOH 2012)

Benzene

- carcinogenicity is a complex mechanism including genotoxic damage, inhibition of DNA repair and altered oncogenic signalling

- leukaemia develops from genotoxic effects in the progenitor cells in the bone marrow, a primary target in benzene-toxicity.

- Do effects on bone marrow cells have a threshold? - Is this an initial and required step to neoplastic disease?

Deriving occupational exposure limits: comparison of approaches1. NOAEL analysis2. BMDL analysis3. Calculation of risks based on exposure response relations

12

Decreased WBC, Granulocyte and Lymphocyte Counts and Benzene Exposure in Previous Month (Lan Q et al., Science 2004)

Benzene exposure Factory B

Feb Mar Apr

May Ju

n JulAugSep Oct

NovDec JanFeb M

ar AprM

ay Jun Ju

lAug

Ben

zene

(P

PM

)

0.1

1

10

100

N= 214 172 209 20 209 194 210 209 207 171 248 138 450 16

2000 2001

Factory B (k=213, n=2667)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

White Blood Cells Granulocytes Lymphocytes

Per

iph

eral

blo

od

cel

l co

un

t

Controls (140)

<1 ppm (109)

1-10 ppm (110)

>10 ppm (31)

Monthly Personal Benzene Exposure Distributions by Factory (Vermeulen et al., 2004)

exposure limits: NOAEL analysis

1. Lan et al., (2004) study high quality study with a balanced design. Data obtained from a representative working population, exposed up to 16 months.

2. mean concentration of 0.57 ppm (1.8 mg/m3) a reduction of neutrophils was reported in the main study.

3. subgroup of 30 workers, not directly exposed to other solvents, with the lowest benzene exposure level measured of 0.29 ± 0.15 ppm (mean ± SD) and a significant reduction in blood cells.

exposure limits: NOAEL analysis

3. uncertainty factor of 3 to take into account the use of a minimal effect level instead of a no-effect level.

4. A LOAEL of 0.3 ppm, results in an HBROEL of 0.3/3 = 0.1 ppm

exposure limits: BMDL analysis

1. Lan et al. (2004) biomarker study was used to estimate exposure levels that are expected to result in a drop of 5% or more in white blood cell populations.

2. Generalized Additive Model (GAM), and was adjusted for age, body mass index (BMI), sex, smoking, alcohol consumption, and presence of infections

Stavanger 2007 16

Spline Regression Analyses of WBC Count and Benzene Exposure

✽ Modeling of data from 247 exposed and 139 control subjects

✽ No apparent threshold✽ Evidence of supralinear

response

exposure limits: BMDL analysis

3. Using the BMDL10 based on the best fitting model (lin-log) for the most sensitive endpoint would result in an estimate of 0.1 ppm as well

Issues in the interpretation of the results

- Other studies that made use of routine benzene exposure and haematological response data (Swaen et al., Chem Biol Interactions, 2010; Tsai et al., Reg Tox Pharmacol, 2004)

- when is a negative an informative negative study? (Ahlbohm et al., 1990)

- study quality issues?- genetic differences?

19

What if benzene is considered a no threshold carcinogen?

✽Benzene example✽Low dose risk

identification✽Low dose response

modeling✽ Identification of

susceptible groups

0.1

1

10

100

1000

< 40 40-200 200-400 > 400

• Currently most dose-response assessments for benzene are based on one study conducted among rubber hydrochloride workers (PLIOFILM)

• Linear extrapolation of findings to exposure levels relevant to the general public

• Problems:

1. Is linear extrapolation justified?

2. Discussion on the quality of the exposure assessment in the PLIOFILM study

Use of evidence from occupational studies in benzene dose-response assessment

Quality of the exposure assessment in the PLIOFILM study

✽ Few exposure measurements✽ Data gaps filled with ‘expert judgment’✽ Large potential for exposure misclassification:

✽ Assigned exposure levels were either to high or too low✽ Assigned exposure levels not very accurate

✽ Difficult to decide what the actual value of this study is for dose-response assessment

Studies included in the meta-regression (Vlaanderen et al., 2010)

SMR

SMR

OR

SMR

SMR

SMR

OR

RR

OR

Risk estimates

Netherlands

USA

U.K.

USA

USA

Italy

Canada

China

Australia

Country

2005Cohort Swaen

2002CohortPliofilm

1997Nested case-controlUK-Petrol

1987CohortWong

2004Cohort DOW

2003Cohort Costantini

1996Nested case-controlCanada petrol

1997Cohort, CAPM-NCI

2003Nested case- controlAustralian Health Watch

YearStudy designStudy

Distribution of the risk estimates (n=30)

Cumulative exposure (ppm-years)

0 100 200 300 400 500 600

lnR

R

0

1

2

3

1

2

Resulting Regression modelsDeviance linear model (1): 29.3 (28 df)

Deviance natural spline (2): 25.8 (27 df)

Flexible model is not linear

Both models predicted an interceptLinear intercept: RR = 1.65 Spline intercept: RR = 1.33

0

500

1000

1500

2000

0 10 20 30 40 50

Benzene, ppm

BO

-Alb

, pm

ol/g

Supralinear shape✽ observed low-dose supralinearity biologically relevant?

• Saturation of benzene-metabolite enzymatic pathways might have induced a supralinear shape

✽ Attenuation of the ERC at higher exposure levels might also have played a role:

• Depletion of susceptible individuals at high exposures• Exposure measurement error• Healthy worker survivor effect • High disease background rates

Cumulative exposure (ppm-years)

0 100 200 300 400 500 600

ln R

R

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Sensitivity analysis: Effect of leaving one study out

Study quality is associated with a n.s. increase in slope of the ERR

(Vlaanderen et al., 2012)

Without CAPM-NCI

Without Pliofilm

Exposure metric Health Watch(*10-3)

AIC Pliofilm(*10-3)

AIC Fold difference

Benzene 98.9p = 0.0007

103.7 5.35p < 0.0001

207.0 18

Sum of metabolites

PBPK model

2.09p = 0.0007

104.4 0.13 p <0.0001

207.5 16

Sumof metabolites

MML model

1.22p = 0.0006

103.9 0.12 p < 0.0001

207.6 10

Sum of metabolites

Regressionsplines model

1.32 p = 0.0005

103.3 0.11 p < 0.0001

207.2 12

Impact of substituting benzene with a measure of benzene metabolism (Vlaanderen Am J Epid 2011)

Risk calculations Health Council

- Meta-analysis benzene as described in Vlaanderen et al. (2010)

- Repeated for leukemia and AML- Cumulative risks of mortality from leukemia and AML were

compared for simulated (hypothetical) cohorts of exposed and unexposed subjects in a life-table analysis

Use of exposure response to calculate exposure limit: Life-table analysis

- All-cause and cause-specific (leukemia/AML) mortality rates identical in the exposed and non-exposed cohorts

- All-cause mortality rates for males: Statistics Netherlands (Statline)

- mortality rates for leukemia and AML: Comprehensive Cancer Centre (IKC).

- Mortality rates modeled using Generalized Additive Model to obtain smooth estimates of average mortality rates by age.

exposure limits: life table analysis

Exposure limits: life table analysis

Benzene exposure levels (ppm) that result in an excess mortality of 4/100.000 (1/1 000 000 per year) at age 75 after occupational exposure from 20-65

Meta-regression model Decay function Leukemia AML

Linear, no intercept None 0.011 0.031

Linear 15yrs 0.020 0.057

Exponential 10yrs 0.013 0.038


Linear, intercept None 0.017 0.044

Linear 15yrs 0.032 0.080



Spline, no intercept None 0.003 0.007

Linear 15yrs 0.005 0.013



Spline, intercept None 0.004 0.009

Linear 15yrs 0.007 0.016



Issues in the calculation of risks

risk diff.✽ Complete follow-up versus age 80: 1-6-1.9 ✽ Use of average rates versus male rates only 0.8-0.9✽ continuous risk after age 65 versus trapezium model 1.5-2.0✽ NHL included versus not included 2.6-3.6✽ Mortality rates UK, EU, NL: no effect

Conclusion

Any approach (NOAEL), BMDL, risk calculations, on the basis of the present information, results in a clear downword pressure for an exposure standard

Strong interplay between epidemiological and toxicological information

Epidemiological information crucial for risk calculations (all approaches make use of human data)

Toxicological interpretation (mechanisms) drives the choice for one of the approaches

04 heederik benzeno

News & Politics