September 29, 2014 Benzene Health Effects Research: What’s New? Schnatter... · 2014. 9. 26. ·...

Benzene Health Effects

Research: What’s New?

September 29, 2014

A. Robert Schnatter, ExxonMobil Biomedical Sciences, Inc

OEMAC Conference, Edmonton, AB

2

• Background – benzene health risks and regulation

• Unanswered questions regarding benzene’s health risks

• Results from recent studies on benzene

• What is myelodysplastic syndrome (MDS)?

• Do we know how benzene produces toxicity/health effects?

• Impact on benzene occupational exposure limits

• 0.5 ppm TWA

• 2.5 ppm STEL

• Are there subpopulations at higher risk?

• Are there medical monitoring tests besides the CBC on the horizon?

Topics: Benzene Health Risk Update

2

3

• Benzene (BZ) recognized as a human leukemogen (i.e. causes leukemia)

• acute myeloid leukemia (AML) – definite link to benzene

• other cell types – designated as “probable” by (IARC, 2010) – debated by others

• non-Hodgkin lymphoma (NHL)• acute and chronic lymphoid leukemia (ALL and CLL)• multiple myeloma

• no mention of myelodysplastic syndrome (MDS) by IARC ) little research

• no mention of other myeloid tumors (myeloproliferative disease)

• insufficeint evidence for chronic myeloid leukemia (CML)

• Benzene has long been known to be a bone marrow toxin and causes hematologic (blood) effects at sufficiently high exposures

• some (but not all) reports show effects (usually mild, possibly reversible) at low (< 1 ppm) levels

• Benzene is clastogenic (causes chromosomal effects)

• genotoxicity results in ‘no safe level’ policy for many regulatory groups

Background: Benzene Health Effects

3

4

Basis for most benzene regulations

4

CASESCONTROLS

HIGH INTENSITYHIGH DURATION

LOW DURATIONLOW INTENSITY

HIGH DURATIONLOW INTENSITY

LOW DURATIONHIGH INTENSITY

Current DayExposure Zone

GOODYEAR PLIOFILM WORKER EXPOSURE MAP

YE

AR

S E

XP

OS

ED

0.1

1.0

10.0

100.0

Mean Exposure Intensity (ppm)

0.1 1.0 10.0 100.0 1000.0

Most BZ risk assessments based on Pliofilm study

• Relatively small study

• All leukemia subtypes

• Little empirical data on lower (

5

Benzene Regulatory StandardsMost regulatory agencies still use pliofilm data to predict excess

disease at lower exposure levels

.

.

.

.

5

• Fifteen total leukemia cases in Pliofilm population (all leukemia sub-types)

• ACGIH: 0.5 ppm (TWA), 2.5 ppm (STEL)

• EPA: 0.04 ppb (24 hr/day, 70 year lifetime)

0

10

20

30

40

0-45 45-400 400-1000 >1000

Cumulative Exposure (ppm-years)1Crump (1994)

Rela

tive

Ris

k (SM

R)

(RR =

1 indic

ate

s n

o e

ffect)

1.22.7 3.1

28.1

l i ne a

r no - t h

r es h

o ld

mo d

e l

Risk of Leukemia

from Pliofilm Study1Extrapolation of Pliofilm Study Risk

to ambient air levels

Pred

icte

d

excess r

isk

ppb over a lifetime

2.5 x 10-2

1 x 10-6

.04 1 1000(1 ppm)

Pliofilm data

6

Data Gap for BZ exposures < 10 ppm

6

CASESCONTROLS

HIGH INTENSITYHIGH DURATION

LOW DURATIONLOW INTENSITY

HIGH DURATIONLOW INTENSITY

LOW DURATIONHIGH INTENSITY

Current DayExposure Zone

GOODYEAR PLIOFILM WORKER EXPOSURE MAP

YE

AR

S E

XP

OS

ED

0.1

1.0

10.0

100.0

Mean Exposure Intensity (ppm)

0.1 1.0 10.0 100.0 1000.0

Current day

exposure zone:

Focus of

pooled analysis

7

L-H disease subtypes

new WHO classification scheme aids research efforts

Dose response

particularly for exposures < 10 ppm

empirical data – linear or non-linear?

Mechanisms of toxicity

like chemotherapeutic agents? role of key enzymes – e.g.

topoisomerase-II? role of bone marrow inflammation/auto-immunity?

Early events

is the complete blood count (CBC) useful?

Key unanswered questions on benzene

7

8

8

RESULTS FROM RECENT STUDIES ON BENZENE

9

References:

1. Schnatter et al., 1996 OEM 53:773-781

2. Rushton et al., 1997 OEM 54:152-166

3. Glass et al., 2003 Epidemiol. 14:569-577

Pooling Three Nested Case Control Studies of Benzene Exposure in Petroleum Workers

Pool data from three previous studies

U.K.2

inconsistent dose

response by subgroups

and exposure metrics

based on 31 LH cancers based on 90 leukemias based on 79 LH cancers

before pooling data � update studies

Canada1

no consistent

dose response, but

small study

Australia3

strong dose response,

especially for AML

60 LH cancers

Incl. 5 MDS

193 LH cancers

Incl. 11 MDS

117 LH cancers

Incl. 13 MDS

370 LH cancers

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Lymphohematopoietic (LH) Cancer: Paradigm Shift Recently Occurred

Traditional Paradigm: Anatomy

• LEUKAEMIAS (CA in peripheral blood)

• LYMPHOMAS (CA in lymph system)

New Paradigm: Cell of Origin

• MYELOID tumours• Myeloproliferative Disease (MPD)

• Myelodysplastic Syndrome (MDS)• Acute Myeloid Leukemias (AML)

• LYMPHOID tumours• B-cells (NHL, CLL, ALL)• T-cells

New paradigm: biologically justified affects new benzene science will

likely affect future benzene regulations

11

Chronic myelogenous leukemia, Ph+ (28)

CIMF chronic myelofibrosis (10)

Polycythemia vera (11)

NOS (7)

Other or unclassifiable MPD (2)

MYELOID

NEOPLASMS

(163)

Myeloproliferative Diseases (58)

MDS/MP Diseases (8)

Myelodysplastic

Syndromes (29)

Acute Leukemias of Ambiguous

Lineage (3)

AML with or without maturation (i.e. M1/M2) (5)

Acute monocytic & acute myelomonocytic leukemia (M4/M5) (3)

Acute erythroid leukemia (i.e. M6) (2)

AML w/recurrent cytogenetic abnormalities (2)

Acute Myeloid

Leukemias (60)

LH cancer classification (WHO scheme)

CMML (6)

RA, RA-EB (8)

Refractory cytopenia w/ML dysplasia (2)

MDS, other (5q-) or unclassifiable (1)

Included in statistical analysis

CML (28)MPD (30)

MDS (29)AML (60)

12

• Define disease(s) of interest (cases)

• Match cases to those who DO NOT have disease of interest (controls)

• Typical matching factors: age, gender, time period

• Determine exposures among both groups (usually back in time)

• “blinding” is important – no knowledge of case/control status

• Compare exposures between cases and matched controls

• If cases are exposed more frequently, or to higher levels, beyond

chance, the exposure could be leading to the disease.

Case-control studies: basic design

12

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•POOLED existing cases and controls

•Added NEW cases and matched controls (4:1 and 5:1) from updated cohort follow-ups to each study• Requested source records (hospital, histology, registry) for all cases• Two hematopathologists re-classified all cases based on source records

•CASE COUNTS: IARC status

• Acute Myeloid Leukemia (AML), n = 60 → Known

• Chronic Myeloid Leukemia (CML), n = 28 → Insufficient

• Chronic Lymphoid Leukemia (CLL), n = 80 → Probable

• Myelodysplastic Syndrome (MDS), n = 29 → Not mentioned

• Myeloproliferative Disease (MPD), n = 30 → Not mentioned

(Pliofilm study: n= 16 “total leukemias”)

Pooled Analysis Study Procedures

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EXPOSURE ASSESSMENT

• Based on >5800 monitoring results over time

• Calculated six exposure metrics: • parts per million x years exposed (ppm-years)• average (ppm)• maximum (ppm)• duration (years)• peak (>3 ppm, 15-60 minutes, weekly)• dermal exposure probablility (H, M, L, N)

INFORMATION QUALITY

• Each exposure estimate scored for certainty (high, medium, low)

• Each diagnosis scored for certainty (high, medium, low)

STATISTICAL ANALYSIS

• Penalized spline models to allow flexible shape of dose-response curves

• Sensitivity analyses on more certain (higher quality) data

Pooled Analysis Study Methods (cont’d)

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• Certainty scores indicated a wide range of diagnostic certainty

• Certainty driven by:

− Specificity of terms in source records

− Documented diagnostic methods

− Amount/type of source material

− Agreement among source records

• Certainty scores:

− AU > CA > UK

− CML/CLL > AML > MPD/MDS

• Sensitivity analyses on more certain cases

Disease Classification

strong moderate least

199

9675

16

Reclassification changed some diagnoses

ORIGINAL DIAGNOSIS % unchanged Revised diagnoses

Leukemia 75% Chronic Leukemia

Acute Leukemia 86% AML

Chronic Leukemia 100%

Lymphoid Leukemia 50% CLL

Myeloid Leukemia 60% AML, MDS

Acute Lymphoid Leukemia 78% CLL, MPD

Acute Myeloid Leukemia 90% MDS, MPD

Chronic Myeloid Leukemia 94% MDS

Chronic Lymphoid Leukemia 100%

Multiple Myeloma 100%

non-Hodgkin Lymphoma 90% ALL, CLL, Lymph NOC.

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Dose Response for AML (spline analysis)

17

0 10 20 30 40

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

Cumulative benzene exposure in ppm-years

Log odds ratio

All exposure historyAll expousre history, high certainty cases95% CI (all exposure history)

All workers (p = 0.46)

More certain diagnoses (p = 0.78)

95% CI (all workers)

Little evidence for dose-response for AML, which is the leukemia

subtype most often linked to benzene exposure.

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Dose Response for CML (spline analysis)

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0 10 20 30 40

-4-2

02

4


Log odds ratio

All exposure history

All expousre history, high certainty cases

95% CI (all exposure history)




No dose response for CML

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Dose Response for CLL (spline analysis)

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0 10 20 30 40

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0


Log odds ratio







No dose response for CLL

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Dose Response for MPD (spline analysis)

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0 10 20 30 40

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5


Log odds ratio







No dose response for MPD

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Dose Response for MDS (spline analysis)

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0 10 20 30 40

-10

12

34

5


Log odds ratio

All exposure historyAll expousre history, high certainty cases





Benzene shows a stronger dose-response for MDS

compared to other endpoints

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Results for Peak Exposure (> 3 ppm weekly exposure for 15-60 minutes for at least one year)

22

0 10

MPD

CML

CLL

MDS

AML

Dx Certainty >2

All Workers

Odds Ratios for Peak Exposures

0.82

0.66

0.97

1.32

0.04

0.41

0.29

0.32

0.68

0.87

2.75

2.43

6.35

30.2

1.14

1.16

1.54

1.71

3.19

6.68

1.5

1.27

2.48

0.70

6.32

0.69

0.69

0.73

1.47

2.41

Peak exposure associated with MDS, but not other

LH cancer subtypes

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Key Analyses for MDS from Pooled Analysis

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Cum. Exp.

(ppm-years) All

High

Dx Certainty

High

Exp. Certainty

2.9 4.3* 11.6* 4.3

Trend Test p=0.01 p=0.004 p=0.10

Avg. Exp.

(ppm)

All High

Dx Certainty

High

Exp. Certainty

0.16-.08 1.99 2.97 3.66

.08-.26 1.85 3.24 1.89

.26+ 3.12 6.10 7.66

Trend Test p=0.08 p=0.04 p=0.08

Max. Exp.

(ppm) All

High

Dx Certainty

High

Exp. Certainty

0.16-.12 1.46 2.13 1.87

.12-.41 1.82 5.89 2.83

>.41 2.81 3.32 8.30

Trend Test p=0.10 p=0.10 p=0.11

Duration

(years)

All High

Dx Certainty

High

Exp. Certainty

≤15.6 1 1 1

15.6-28 0.77 0.85 0.57

>28 1.74 3.34 0.44

Trend Test p=0.22 p=0.08 p=0.69

Peak

Exposure

All High

Dx Certainty

High

Exp. Certainty

> 3ppm 2.48

p=0.06

6.32*

p=0.02

5.74*

p=0.04

Dermal

Exposure

All High

Dx Certainty

High

Exp. Certainty

Hi Prob. 2.15

p=0.14

3.31

p=0.09

6.69

p=0.10

Strongest relationships: cumulative exposure and peak exposure metrics.

When both metrics are considered in a single model, only peak exposure

remains statistically significant.

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Key Analyses for MDS from Pooled Analysis

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Spline analysis is more robust statistical measure

� Tertile analysis point of significance 2.93 not significant in spline analysis

� More robust spline analysis indicate borderline significance between 9 and

75 ppm-yrs

� 9 ppm-y / 25 y = 0.4 ppm LTA (based on study population)

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Pooled Analysis MDS Cases / Controls

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• MDS cases over-represented (beyond 4-5:1 matching ratio) at

higher maximum (>0.7 ppm) benzene concentrations.

Current

day

exposure

zone

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• These results are believed to represent a real association between benzene and MDS at lower levels than previously reported

• Higher concentrations of benzene may be necessary to affect AML

• Future studies on benzene should include MDS as a potential outcome and seek to measure benzene exposure, smoking, and individual susceptibility factors as precisely as possible.

ConclusionsSummary: pooled nested case control

study of benzene exposure

JRN1

JRN1 Is it deemed necessary to have these two sub-bullets on the slide?Nacheman, Jessica R, 19/09/2014

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• In 2012, the EM Occupational Exposure Limit committee considered the pooled analysis findings and:

• Retired the Benzene ACGIH TLV (0.5 ppm TWA / 2.5 ppm STEL)

• Adopted a new OEL (0.5 ppm TWA / 1 ppm STEL)

• Reasons for lowering the STEL from 2.5 to 1 ppm:

• Indications that peak exposures were important in pooled analysis

• Supporting information from biologic considerations (PBPK models)

• Reasons for maintaining a TWA of 0.5 ppm:

• peak exposure metric more robust than intensity metrics in a joint risk model• observed intensity effects believed to be linked to peak exposures

• Excess MDS not seen for more continuous exposures (e.g. refinery workers)

• 0.5 ppm TWA is presently implemented in a way that does not allow full shift concentrations close to 0.5 ppm

• In an environment with prevalent episodic (rather than continuous) exposure scenarios, lowering the STEL may be an efficient way to lower overall exposures

Impact on Occupational Exposure Limits

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• MDS is a ‘relatively’ new disease (1982- FAB, 2001 and 2008- WHO)

• US cases: 1500 cases (1995) ; 15,000 cases (2003) (Ma, 2012)

• Diagnosis requires histopathologic examination of the bone marrow (1970’s ff)

• Likely misclassified as aplastic anemia, myeloproliferative diseases or other LH in the past

• Formerly known as “pre-leukemia” (also “smoldering leukemia”)

• Now known that only 20-30% progress to leukemia

• Reportable to US (and other) cancer registries as of 2001 (now technically a “cancer”)

What is Myelodysplastic Syndrome (MDS)?

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�RA�RARS�RCMD�RAEB�MDS del (5q)�MDS unclassifiable

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MDS Incidence is age-dependent

Reference: Ma X. Epidemiology of myelodysplastic syndromes. Amer J Medicine 2012; 125:S2-S5.

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MDS Risk Factor: Smoking

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MDS Survival by Sub-Type

Reference: Ma X. Myelodysplastic syndromes. Incidence and survival in the United States. Cancer 2007; 109:1536-1542.

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Author (year) Exposures Odds Ratio 95% Confidence

Interval

Hayes (1997) 7 cases of MDS in exposed (0 unexposed). 5 exposed to >40

ppm-yrs benzene

∞ 1.7 - ∞

Albin (2003) ‘Ever’ vs never exposed 0.95 0.54 – 1.7

Irons (2010) >21 ppm 11.1

(MDS-U

case/

case)

1.34-92.4

Schnatter (2012) < 0.35ppm-yr

0.35-2.93 ppm-yr

> 2.93 ppm-yr

1.00

1.73

4.33

(ref)

0.55-5.47

1.41-14.3

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Benzene and Myelodysplastic Syndrome

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• Biologic basis for BZ/MDS

• MDS, like AML, derives from the myeloid cell line• MDS can evolve into AML• Both MDS and AML are caused by chemotherapeutic agents • MDS is a clonal disease characterized by bone marrow dysfunction, often with

associated cytopenias (which are effects of benzene)

• Whether AML is an independent effect or a possible outcome in benzene-induced MDS (or both) remains unresolved.

• Higher benzene exposures may be necessary for significant risks of AML to occur (e.g. AML may be an independent effect)

• Since MDS frequently evolves into AML, MDS could be a precursor to benzene-induced AML.

Benzene and Myelodysplastic Syndrome

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How does benzene exert effects?

(mode or mechanism of action)

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BID vs. de-novo MDS (Myelodysplastic Syndrome)

BID de-novo MDS

26% have normal peripheral blood counts

No myeloid clonal genetic abnormalities

Hypocellular bone marrow

� dysplastic eosinophilic precursor cells*

Severe dyserythropoiesis common*

Hematophagocytosis*

Robust T-cell response, clones in half*

Peripheral blood abnormalities required

26% myeloid clonal genetic abn. (e.g. 5q-, 7q-)

Hypercellular & hypocellular bone marrow

Less dysplatic eosinophilic precursors

Dyserythropoiesis less severe/common

Not usually seen

More moderate T-cell response, clones rare

23 cases of benzene-induced dysplasia (BID) exposed to high levels of BZ (Shanghai)

Most would likely qualify as a type of MDS if not recognized as unique subtype

* Indicative of an autoimmune and/or inflammatory disease process

If true, which candidate genes would indicate autoimmune response?

Irons et al., 2005

36

• cytokine involved in:

• immune and inflammatory responses

• apoptosis checks and balances

• hematopoiesis (blood formation)

• TNF- α is over-expressed in:

• rheumatoid arthritis, psoriasis (autoimmune dx’s)

• aplastic anemia

• MDS (also some conflicting data)

• located on chromosome 6, four prominent SNPs in promoter region

36

TNF-α

Transcription

Start Site

-863 -857 -308 -238(C�A) (C�T) (G�A) (G�A)

tumor necrosis factor-α: a candidate gene

37

Study design: Lv et al. 2007, benzene-MDS

informed consent

questionnaire

blood collected

Genomic DNA

TNF-αSNPs

examine if TNF-α related to diseases

gather workplace BZ dataage, gender, smoking, alcohol use,

BZ exposure

exclude conditions related to auto-

immunity, e.g., arthritis, drug use,

nutritional anemia, etc.

% >30 ppm avg. ppm

BID: 100% 305

BP: 65% 123

Others(MDS): 0% 0

46 cases of

Benzene

Poisoning (BP)

95 cases of denovo

Myelodysplastic

Syndrome (MDS)

23 cases of

Benzene-induced

Dysplasia (BID)

38

results: risks of TNF-α SNPs by disease

38

0.01

0.1

1

10

Re

lative

Ris

k v

s.

Co

ntr

ols

-238A -308A -857T -863A

1.77

2.23

1.42

0.93

2.93

Myelodysplastic

Syndrome

Benzene

Poisoning

Benzene-induced

Myelo-dysplasia

0

0.38

0.68

1.23

0.29

0.57

7.6

39

• Benzene-induced dysplasia (BID),a type of MDS, involves bone marrow

inflammation, abnormal hematopoiesis, and a role for autoimmunity

• TNF-α has key role in some autoimmune diseases

• One of four TNF-α SNPs, namely -238A, is related to certain types of

MDS

• This relationship provides further support for the role of autoimmunity in

MDS

Summary of mechanistic studies

39

40

Prospects for useful biomarkers

Susceptibility

• TNF-α 238A genetic polymorphisms

Risk of evolving MDS

• Early autoimmune changes

• Increase in CD8+ cytotoxic T-cell lymphocytes (CTL)

• Clonal/oligoclonal expansion of BM CD8+ CTL

• Can be measured in peripheral blood*

• Expansion of distinct clones indicate previous response in

bone marrow

* Risitano AM et al (2002) Oligoclonal and polyclonal CD4 and CD8 lymphocytes in AA and PNH measured by Vβ CDR3 spectratyping and flow cytometry. Blood 100: 178-183

41

• SNP’s of key genes

• TNF-α (immune response)

• MPO (metabolism)

• NQO1 (detoxification)

• Males > females

• Slower excretion

• Asian populations

• Blood effects more prominent – ALDH?

• Smokers

• Another source of BZ, potentiation?

Potential groups at higher risk

41

42

• Recent studies show elevated MDS in BZ exposed workers

• MDS a relatively “new” disease, can progress to AML, strong age effect

• Key events for benzene toxicity still unknown, bone marrow

inflammation/autoimmunity may be key

• Recent findings could impact OEL’s

• At-risk populations still uncertain

• Cytotoxic t-lymphocytes offer promise as a useful biomarker

Summary

43

AcknowledgementsCo-principal investigators:

Lesley Rushton, Imperial College London

Deborah Glass, Monash University Melbourne Australia

Disease classification team included:

John Ryder University of Colorado

Richard Irons University of Colorado

Malcolm Sim Monash University

Statistical Analysis team included:

Gong Tang University of Pittsburgh

Min Chen ExxonMobil Biomedical Sciences

Susan Marcella ExxonMobil Biomedical Sciences

Exposure assessment team included:

Dave Verma McMaster University

Tom Armstrong TWA8hr, formerly ExxonMobil Biomedical Sciences

Eileen Pearlman retired, formerly ExxonMobil Biomedical Sciences

• Funders: CONCAWE, API

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• Pooled Analysis study: Journal of the National Cancer Institute

• http://jnci.oxfordjournals.org/content/early/recent

• More on MDS: American Cancer Society

• http://www.cancer.org/Cancer/MyelodysplasticSyndrome/DetailedGuide/myel

odysplastic-syndromes-what-is-m-d-s

• More on benzene: ATSDR

• http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=40&tid=14

• http://www.atsdr.cdc.gov/toxfaqs/tf.asp?id=38&tid=14

Resources

44

Thank-you! Questions?

46

back-up/supplemental material

46

48

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Nilsson PG, Mitelman F, Hagmar L. 2003. Cytogenetic and morphologic subgroups of myelodysplastic syndromes in

relation to occupational and hobby exposures. Scand J Work Environ Health 29:378-387.

Du Y, Fryzek J, Sekeres MA, Taioli E. 2010. Smoking and alcohol intake as risk factors for myelodysplastic syndromes

(MDS). Leuk Res 34:1-5.

Glass DC, Gray CN, Jolley DJ, Gibbons C, Sim MR, Fritschi L, Adams GG, Bisby JA and Manuell R (2003) Leukemia

risk associated with low-level benzene exposure Epidemiol. 14:569-577

Hayes RB, Yin S, Dosemeci M, Li G-L, Wacholder S. 1997. Benzene and the dose-related incidence of hematologic

neoplasms in China. JNCI 89:1065-1071.

Irons RD, Lv L, Gross SA, Ye X, Bao L, Wang XQ, Ryder J, Armstrong TW, Zhou Y Miao L Le AT Kerzic PJ, Ni W and Fu

H (2005) Chronic exposure to benzne results in a unique form of dysplasia Leukemia Research, 29(12):1371-1380

Irons RD, Gross SA, Le A, Wang XQ, Chen Y, Ryder J, Schnatter AR (2010) Integrating WHO 2001-2008 criteria for the

diagnosis of Myelodysplastic Syndrome (MDS): a case-case analysis of benzene exposure. Chem Biol Interact 184:30-

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to benzene Leukemia Res.

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Risitano AM et al (2002) Oligoclonal and polyclonal CD4 and CD8 lymphocytes in AA and PNH measured by Vb CDR3

spectratyping and flow cytometry. Blood 100: 178-183.

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benzene in petroleum marketing and distribution workers in the United Kingdom Occ Env Med 54: 152-166

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workers.

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Schnatter AR, Nicolich MJ, Bird MG (1996) Determination of leukemogenic benzene exposure concentrations: Refined

analyses of the Pliofilm cohort. Risk Anal 16: 833-40

Schnatter AR, Glass DC, Tang G, Irons RD, Rushton L. (2012) Myelodysplastic Syndrome and Benzene Exposure Among Petroleum Workers: An International Pooled Analysis. J Natl Cancer Inst.

Yin S, Hayes RB, Linet MS, Dosemeci M, Wacholder S, Blot WJ. (1996) A cohort study of cancer among benzene-exposed workers in China: overall results. Amer J Indust Med 29:227-235.

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