1

1. Exposure Data

1.1 Identification of the agent

1.1.1 Nomenclature

Chem. Abstr. Serv. Reg. No.: 1071-83-6 (acid); also relevant:38641-94-0 (glyphosate-isopropylamine salt)40465-66-5 (monoammonium salt)69254-40-6 (diammonium salt)34494-03-6 (glyphosate-sodium)81591-81-3 (glyphosate-trimesium)Chem. Abstr. Serv. Name: N-(phosphono-methyl)glycinePreferred IUPAC Name: N-(phosphono-methyl)glycineSynonyms: Gliphosate; glyphosate; glypho-sate hydrochloride; glyphosate [calcium, copper (2+), dilithium, disodium, magne-sium, monoammonium, monopotassium, monosodium, sodium, or zinc] saltTrade names: Glyphosate products have been sold worldwide under numerous trade names, including: Abundit Extra; Credit; Xtreme; Glifonox; Glyphogan; Ground-Up; Rodeo; Roundup; Touchdown; Tragli; Wipe Out; Yerbimat (Farm Chemicals International, 2015).

1.1.2 Structural and molecular formulae and relative molecular mass

H2CP

OHO

OHN

H

CH2

C

OHO

Molecular formula: C3H8NO5PRelative molecular mass: 169.07Additional information on chemical struc-

ture is also available in the PubChem Compound database (NCBI, 2015).

1.1.3 Chemical and physical properties of the pure substance

Description: Glyphosate acid is a colour-less, odourless, crystalline solid. It is formulated as a salt consisting of the deprotonated acid of glyphosate and a cation (isopropylamine, ammon - ium, or sodium), with more than one salt in some formulations.Solubility: The acid is of medium solubility at 11.6 g/L in water (at 25 °C) and insoluble in common organic solvents such as acetone, ethanol, and xylene; the alkali-metal and

GLYPHOSATE

IARC MonogRAphs – 112

2

amine salts are readily soluble in water (Tomlin, 2000).Volatility: Vapour pressure, 1.31 × 10−2 mPa at 25 °C (negligible) (Tomlin, 2000).Stability: Glyphosate is stable to hydrolysis in the range of pH 3 to pH 9, and relatively stable to photodegradation (Tomlin, 2000). Glyphosate is not readily hydrolysed or oxidized in the field (Rueppel et al. 1977). It decomposes on heating, producing toxic fumes that include nitrogen oxides and phos-phorus oxides (IPCS, 2005).Reactivity: Attacks iron and galvanized steel (IPCS, 2005).Octanol/water partition coefficient (P): log P,

glyphosate

3

facilitate uptake by plants (Székács & Darvas, 2012). Formulations might contain other active ingredients, such as simasine, 2,4-dichlorophen-oxyacetic acid (2,4-D), or 4-chloro-2-methyl-phenoxyacetic acid (IPCS, 1996), with herbicide resistance driving demand for new herbicide formulations containing multiple active ingredi-ents (Freedonia, 2012).

(b) Production volume

Glyphosate is reported to be manufactured by at least 91 producers in 20 countries, including 53 in China, 9 in India, 5 in the USA, and others in Australia, Canada, Cyprus, Egypt, Germany, Guatemala, Hungary, Israel, Malaysia, Mexico, Singapore, Spain, Taiwan (China), Thailand, Turkey, the United Kingdom, and Venezuela (Farm Chemicals International, 2015). Glyph-osate was registered in over 130 countries as of 2010 and is probably the most heavily used herbi-cide in the world, with an annual global produc-tion volume estimated at approximately 600 000 tonnes in 2008, rising to about 650 000 tonnes in 2011, and to 720 000 tonnes in 2012 (Dill et al., 2010; CCM International, 2011; Hilton, 2012; Transparency Market Research, 2014).

Production and use of glyphosate have risen dramatically due to the expiry of patent protec-tion (see above), with increased promotion of non-till agriculture, and with the introduction in 1996 of genetically modified glyphosate-tol-erant crop varieties (Székács & Darvas, 2012). In the USA alone, more than 80 000 tonnes of glyphosate were used in 2007 (rising from less than 4000 tonnes in 1987) (EPA, 1997, 2011). This rapid growth rate was also observed in Asia, which accounted for 30% of world demand for glyphosate in 2012 (Transparency Market Research, 2014). In India, production increased from 308 tonnes in 2003–2004, to 2100 tonnes in 2007–2008 (Ministry of Chemicals & Fertilizers, 2008). China currently produces more than 40% of the global supply of glyphosate, exports almost 35% of the global supply (Hilton, 2012),

and reportedly has sufficient production capacity to satisfy total global demand (Yin, 2011).

1.2.2 Uses

Glyphosate is a broad-spectrum, post-emergent, non- selective, systemic herbicide, which effectively kills or suppresses all plant types, including grasses, perennials, vines, shrubs, and trees. When applied at lower rates, glyphosate is a plant-growth regulator and desiccant. It has agricultural and non-agricul-tural uses throughout the world.

(a) Agriculture

Glyphosate is effective against more than 100 annual broadleaf weed and grass species, and more than 60 perennial weed species (Dill et al., 2010). Application rates are about 1.5–2  kg/ha for pre-harvest, post-planting, and pre-emer-gence use; about 4.3 kg/ha as a directed spray in vines, orchards, pastures, forestry, and industrial weed control; and about 2  kg/ha as an aquatic herbicide (Tomlin, 2000). Common application methods include broadcast, aerial, spot, and directed spray applications (EPA, 1993a).

Due to its broad-spectrum activity, the use of glyphosate in agriculture was formerly limited to post-harvest treatments and weed control between established rows of tree, nut, and vine crops. Widespread adoption of no-till and conservation-till practices (which require chemical weed control while reducing soil erosion and labour and fuel costs) and the intro-duction of transgenic crop varieties engineered to be resistant to glyphosate have transformed glyphosate to a post-emergent, selective herbi-cide for use on annual crops (Duke & Powles, 2009; Dill et al. 2010). Glyphosate-resistant transgenic varieties have been widely adopted for the production of corn, cotton, canola, and soybean (Duke & Powles, 2009). Production of such crops accounted for 45% of worldwide demand for glyphosate in 2012 (Transparency Market Research, 2014). However, in Europe,

IARC MonogRAphs – 112

4

where the planting of genetically modified crops has been largely restricted, post-harvest treat-ment is still the most common application of glyphosate (Glyphosate Task Force, 2014). Intense and continuous use of glyphosate has led to the emergence of resistant weeds that may reduce its effectiveness (Duke & Powles, 2009).

(b) Residential use

Glyphosate is widely used for household weed control throughout the world. In the USA, glyphosate was consistently ranked as the second most commonly used pesticide (after 2,4-D) in the home and garden market sector between 2001 and 2007, with an annual use of 2000–4000 tonnes (EPA, 2011).

(c) Other uses

Glyphosate was initially used to control perennial weeds on ditch banks and roadsides and under power lines (Dill et al., 2010). It is also used to control invasive species in aquatic or wetland systems (Tu et al., 2001). Approximately 1–2% of total glyphosate use in the USA is in forest management (Mance, 2012).

Glyphosate has been used in a large-scale aerial herbicide-spraying programme begun in 2000 to reduce the production of cocaine in Colombia (Lubick, 2009), and of marijuana in Mexico and South America (Székács & Darvas, 2012).

(d) Regulation

Glyphosate has been registered for use in at least 130 countries (Dill et al., 2010). In the USA, all uses are eligible for registration on the basis of a finding that glyphosate “does not pose unreasonable risks or adverse effects to humans or the environment” (EPA, 1993a). A review conducted in 2001 in connection with the regis-tration process in the European Union reached similar conclusions regarding animal and human safety, although the protection of groundwater

during non-crop use was identified as requiring particular attention in the short term (European Commission, 2002).

Nevertheless, as worldwide rates of adoption of herbicide-resistant crops and of glyphosate use have risen in recent years (Duke & Powles, 2009), restriction of glyphosate use has been enacted or proposed in several countries, although docu-mented actions are few. In 2013, the Legislative Assembly of El Salvador voted a ban on the use of pesticides containing glyphosate (República de El Salvador, 2013). Sri Lanka is reported to have instituted a partial ban based on an increasing number of cases of chronic kidney disease among agricultural workers, but the ban was lifted after 2 months (ColomboPage, 2014). The reasons for such actions have included the development of resistance among weed species, as well as health concerns.

No limits for occupational exposure were identified by the Working Group.

1.3 Measurement and analysis

Several methods exist for the measurement of glyphosate and its major metabolite aminomethyl phosphonic acid (AMPA) in various media, including air, water, urine, and serum (Table 1.1). The methods largely involve derivatization with 9-fluorenylmethyl chloro formate (FMOC-Cl) to reach sufficient retention in chromatographic columns (Kuang et al., 2011; Botero-Coy et al., 2013). Chromatographic techniques that do not require derivatization and enzyme-linked immuno- sorbent assays (ELISA) are under development (Sanchís et al., 2012).

glyphosate

5

1.4 occurrence and exposure

1.4.1 Exposure

(a) Occupational exposure

Studies related to occupational exposure to glyphosate have included farmers and tree nursery workers in the USA, forestry workers in Canada and Finland, and municipal weed-con-trol workers in the United Kingdom (Centre de Toxicologie du Québec, 1988; Jauhiainen et al., 1991; Lavy et al., 1992; Acquavella et al., 2004; Johnson et al., 2005). Para-occupational expo-sures to glyphosate have also been measured in

farming families (Acquavella et al., 2004; Curwin et al., 2007). These studies are summarized in Table 1.2.

(b) Community exposure

Glyphosate can be found in soil, air, surface water, and groundwater (EPA, 1993a). Once in the environment, glyphosate is adsorbed to soil and is broken down by soil microbes to AMPA (Borggaard & Gimsing, 2008). In surface water, glyphosate is not readily broken down by water or sunlight (EPA, 1993a). Despite extensive worldwide use, there are relatively few studies

Table 1.1 Methods for the analysis of glyphosate

Sample matrix Assay procedure Limit of detection Reference

Water HPLC/MS (with online solid-phase extraction)

0.08 µg/L Lee et al. (2001)

ELISA 0.05 µg/L Abraxis (2005)LC-LC-FD 0.02 µg/L Hidalgo et al. (2004)Post HPLC column derivatization and FD

6.0 µg/L EPA (1992)

UV visible spectrophotometer (at 435 ng)

1.1 µg/L Jan et al. (2009)

Soil LC–MS/MS with triple quadrupole

0.02 mg/kg Botero-Coy et al. (2013)

Dust GC-MS-MID 0.0007 mg/kg Curwin et al. (2005)Air HPLC/MS with online solid-

phase extraction0.01 ng/m3 Chang et al. (2011)

Fruits and vegetables HILIC/WAX with ESI-MS/MS 1.2 µg/kg Chen et al. (2013)Field crops (rice, maize and soybean)

LC–ESI-MS/MS 0.007–0.12 mg/kg Botero-Coy et al. (2013b)

Plant vegetation HPLC with single polymeric amino column

0.3 mg/kg Nedelkoska & Low (2004)

Serum LC–MS/MS 0.03 µg/mL 0.02 µg/mL (aminomethylphosphonic acid) 0.01 µg/mL (3-methylphosphinicopropionic acid)

Yoshioka et al. (2011)

Urine HPLC with post-column reaction and FD

1 µg/L Acquavella et al. (2004)

ELISA 0.9 µg/L Curwin et al. (2007)ELISA, enzyme-linked immunosorbent assay; ESI-MS/MS, electrospray tandem mass spectrometry; FD, fluorescence detection; GC-MS-MID, gas chromatography-mass spectrometry in multiple ion detection mode; HILIC/WAX, hydrophilic interaction/weak anion-exchange liquid chromatography; HPLC/MS, high-performance liquid chromatography with mass spectrometry; HPLC, high-performance liquid chromatography; LC-ESI–MS/MS, liquid chromatography-electrospray–tandem mass spectrometry; LC–LC, coupled-column liquid chromatography; LC–MS/MS, liquid chromatography–tandem mass spectrometry

IARC MonogRAphs – 112

6

Tabl

e 1.

2 O

ccup

atio

nal a

nd p

ara-

occu

pati

onal

exp

osur

e to

gly

phos

ate

Indu

stry

, co

untr

y, y

ear

Job/

proc

ess

Res

ults

Com

men

ts/a

ddit

iona

l dat

aR

efer

ence

Fore

stry

Can

ada,

198

6A

rith

met

ic m

ean

of a

ir g

lyph

osat

e co

ncen

trat

ions

:A

ir c

once

ntra

tions

of g

lyph

osat

e w

ere

mea

sure

d at

the

wor

k sit

es o

f one

cre

w (fi

ve

wor

kers

) dur

ing

grou

nd sp

rayi

ng

268

urin

e sa

mpl

es w

ere

colle

cted

from

40

wor

kers

; gly

phos

ate

conc

entr

atio

n w

as a

bove

th

e LO

D (1

5 µg

/L) i

n 14

%

Cen

tre

de T

oxic

olog

ie

du Q

uébe

c (1

988)

Sign

alle

rM

orni

ng, 0

.63

µg/m

3 A

ftern

oon,

2.2

5 µg

/m3

Ope

rato

rM

orni

ng, 1

.43

µg/m

3 A

ftern

oon,

6.4

9 µg

/m3

Ove

rsee

rM

orni

ng, 0

.84

µg/m

3 A

ftern

oon,

2.4

1 µg

/m3

Mix

erM

orni

ng, 5

.15

µg/m

3 A

ftern

oon,

5.4

8 µg

/m3

Finl

and,

yea

r NR

Wor

kers

per

form

ing

silv

icul

tura

l cle

arin

g (n

= 5

)

Rang

e of

air

gly

phos

ate

conc

entr

atio

ns,

glyphosate

7

Indu

stry

, co

untr

y, y

ear

Job/

proc

ess

Res

ults

Com

men

ts/a

ddit

iona

l dat

aR

efer

ence

Farm

ing

USA

, 200

1O

ccup

atio

nal a

nd

para

-occ

upat

iona

l ex

posu

re o

f 24

farm

fam

ilies

(24

fath

ers,

24 m

othe

rs

and

65 c

hild

ren)

. C

ompa

riso

n gr

oup:

25

non

-far

m fa

mili

es

(23

fath

ers,

24

mot

hers

and

51

child

ren)

Geo

met

ric

mea

n (r

ange

) of g

lyph

osat

e co

ncen

trat

ions

in u

rine

: N

on-f

arm

fath

ers,

1.4

µg/L

(0.1

3–5.

4)

Farm

fath

ers,

1.9

µg/L

(0.0

2–18

) N

on-f

arm

mot

hers

, 1.2

µg/

L (0

.06–

5.0)

Fa

rm m

othe

rs, 1

.5 µ

g/L

(0.1

0–11

) N

on-f

arm

chi

ldre

n, 2

.7 µ

g/L

(0.1

0–9.

4)

Farm

chi

ldre

n, 2

.0 µ

g/L

(0.0

2–18

)

Freq

uenc

y of

gly

phos

ate

dete

ctio

n ra

nged

fr

om 6

6% to

88%

of s

ampl

es (o

bser

ved

conc

entr

atio

ns b

elow

the

LOD

wer

e no

t ce

nsor

ed).

Det

ectio

n fr

eque

ncy

and

geom

etri

c m

ean

conc

entr

atio

n w

ere

not s

igni

fican

tly

diffe

rent

bet

wee

n fa

rm a

nd n

on-f

arm

fam

ilies

(o

bser

ved

conc

entr

atio

ns b

elow

the

LOD

wer

e no

t cen

sore

d)

Cur

win

et a

l. (2

007)

USA

, yea

r NR

Occ

upat

iona

l and

pa

ra-o

ccup

atio

nal

expo

sure

s of 4

8 fa

rmer

s, th

eir

spou

ses,

and

79

child

ren

Geo

met

ric

mea

n (r

ange

) of g

lyph

osat

e co

ncen

trat

ion

in u

rine

on

day

of

appl

icat

ion:

Fa

rmer

s, 3.

2 µg

/L (<

 1 to

233

µg/

L)

Spou

ses,

NR

(< 1

to 3

µg/

L)

Chi

ldre

n, N

R (<

 1 to

29

µg/L

)

24-h

our c

ompo

site

urin

e sa

mpl

es fo

r eac

h fa

mily

mem

ber t

he d

ay b

efor

e, th

e da

y of

, an

d fo

r 3 d

ays a

fter a

gly

phos

ate

appl

icat

ion.

G

lyph

osat

e w

as d

etec

ted

in 6

0% o

f far

mer

s’ sa

mpl

es, 4

% o

f spo

uses

’ sam

ples

and

12%

of

child

ren’

s sam

ples

the

day

of sp

rayi

ng a

nd

in 2

7% o

f far

mer

s’ sa

mpl

es, 2

% o

f spo

uses

’ sa

mpl

es a

nd 5

% o

f chi

ldre

n’s s

ampl

es 3

 day

s aft

er

Acq

uave

lla et

al.

(200

4)

LOD

, lim

it of

det

ectio

n; N

D, n

ot d

etec

ted;

NR

, not

repo

rted

Tabl

e 1.

2 (

cont

inue

d)

IARC MonogRAphs – 112

8

on the environmental occurrence of glyphosate (Kolpin et al., 2006).

(i) AirVery few studies of glyphosate in air were

available to the Working Group. Air and rain-water samples were collected during two growing seasons in agricultural areas in Indiana, Mississippi, and Iowa, USA (Chang et al., 2011). The frequency of glyphosate detection ranged from 60% to 100% in air and rain samples, and concentrations ranged from

glyphosate

9

Tabl

e 1.

3 Co

ncen

trat

ion

of g

lyph

osat

e an

d A

MPA

in w

ater

Cou

ntry

, yea

r of

sam

plin

gN

umbe

r of s

ampl

es/s

etti

ngR

esul

tsC

omm

ents

/add

itio

nal d

ata

Ref

eren

ce

USA

, 200

251

stre

ams/

agri

cultu

ral a

reas

(1

54 sa

mpl

es)

Max

imum

gly

phos

ate

conc

entr

atio

n, 5

.1 μ

g/L

Max

imum

AM

PA c

once

ntra

tion,

3.

67 μ

g/L

The

sam

ples

wer

e ta

ken

follo

win

g pr

e- a

nd p

ost-

emer

genc

e ap

plic

atio

n an

d du

ring

har

vest

se

ason

G

lyph

osat

e de

tect

ed in

36%

of

sam

ples

; AM

PA d

etec

ted

in 6

9%

of sa

mpl

es

Batt

aglin

et a

l., (2

005)

USA

, 200

210

was

tew

ater

trea

tmen

t pla

nts

and

two

refe

renc

e st

ream

s (40

sa

mpl

es)

Gly

phos

ate,

rang

e ≤ 

0.1–

2 μg

/L

AM

PA, r

ange

≤ 0

.1–4

μg/

LA

MPA

was

det

ecte

d m

ore

freq

uent

ly (6

7.5%

) tha

n gl

ypho

sate

(17.

5%)

Kol

pin

et a

l. (2

006)

Can

ada,

200

23

wet

land

s and

10

agri

cultu

ral

stre

ams (

74 sa

mpl

es)

Rang

e, <

 0.0

2–6.

08 μ

g/L

Gly

phos

ate

was

det

ecte

d in

mos

t of

the

wet

land

s and

stre

ams (

22%

of

sam

ples

)

Hum

phri

es et

al.

(200

5)

Col

ombi

a, y

ear N

R5

area

s nea

r cro

ps a

nd c

oca

erad

icat

ion

(24

sam

ples

)M

axim

um c

once

ntra

tion,

30

.1 μ

g/L

(min

imum

and

mea

n,

NR)

Gly

phos

ate

dete

cted

in 8

% o

f sa

mpl

es (M

DL,

25 

μg/L

)So

lom

on et

al.,

(200

7)

Den

mar

k, 2

010–

2012

4 ag

ricu

ltura

l site

s (45

0 sa

mpl

es)

Rang

e, <

 0.1

–31.

0 μg

/LG

lyph

osat

e de

tect

ed in

23%

of

sam

ples

; AM

PA d

etec

ted

in 2

5%

of sa

mpl

es

Brüc

h et

al.

(201

3)

AM

PA, a

min

omet

hylp

hosp

honi

c ac

id; M

DL,

met

hod

dete

ctio

n lim

it; N

R, d

ata

not r

epor

ted

IARC MonogRAphs – 112

10

Tabl

e 1.

4 Co

ncen

trat

ions

of g

lyph

osat

e in

food

Cou

ntry

, yea

rTy

pe o

f foo

dR

esul

tsC

omm

ents

/add

itio

nal d

ata

Ref

eren

ce

Den

mar

k, 1

998,

199

9C

erea

ls> 

50%

of s

ampl

es h

ad d

etec

tabl

e re

sidue

s M

eans

: 0.0

8 m

g/kg

in 1

999

and

0.11

mg/

kg in

199

8

49 sa

mpl

es o

f the

199

8 ha

rves

t 46

sam

ples

of t

he 1

999

harv

est

Gra

nby

& V

ahl (

2001

)

27 E

urop

ean

Uni

on

mem

ber s

tate

s, N

orw

ay

and

Icel

and,

200

7

350

diffe

rent

food

co

mm

oditi

es0.

04%

of 2

302

frui

t, ve

geta

ble

and

cere

al sa

mpl

es

9.5%

of 4

09 c

erea

l sam

ples

74 3

05 to

tal s

ampl

esEF

SA (2

009)

Aus

tral

ia, 2

006

Com

posit

e sa

mpl

e of

food

s co

nsum

ed in

24

hour

s75

% o

f sam

ples

had

det

ecta

ble

resid

ues

Mea

n, 0

.08

mg/

kg

Rang

e, <

 0.0

05 to

0.5

mg/

kg

20 to

tal s

ampl

es fr

om 4

3 pr

egna

nt w

omen

McQ

ueen

et a

l. (2

012)

Tabl

e 1.

5 Co

ncen

trat

ions

of g

lyph

osat

e an

d A

MPA

in u

rine

and

ser

um in

the

gene

ral p

opul

atio

n

Cou

ntry

, per

iod

Subj

ects

Res

ults

Com

men

ts/a

ddit

iona

l dat

aR

efer

ence

Uri

ne18

Eur

opea

n co

untr

ies,

2013

162

indi

vidu

als

Ari

thm

etic

mea

n of

gly

phos

ate

conc

entr

atio

n:

0.21

µg/

L (m

axim

um, 1

.56 

µg/L

) A

rith

met

ic m

ean

of A

MPA

co

ncen

trat

ion:

0.

19 µ

g/L

(max

imum

, 2.6

3 µg

/L)

44%

of s

ampl

es h

ad q

uant

ifiab

le

leve

ls of

gly

phos

ate

and

36%

had

qu

antifi

able

leve

ls of

AM

PA

MLH

B (2

013)

Col

ombi

a, 2

005–

2006

112

resid

ents

of a

reas

sp

raye

d fo

r dru

g er

adic

atio

n

Ari

thm

etic

mea

n (r

ange

) of

glyp

hosa

te c

once

ntra

tion:

7.

6 µg

/L (N

D–1

30 µ

g/L)

A

rith

met

ic m

ean

(ran

ge) o

f AM

PA

conc

entr

atio

n:

1.6

µg/L

(ND

–56 

µg/L

)

40%

of s

ampl

es h

ad d

etec

tabl

e le

vels

of g

lyph

osat

e an

d 4%

had

de

tect

able

leve

ls of

AM

PA (L

OD

s, 0.

5 an

d 1.

0 µg

/L, r

espe

ctiv

ely)

U

rina

ry g

lyph

osat

e w

as a

ssoc

iate

d w

ith u

se in

agr

icul

ture

Varo

na et

al.

(200

9)

Seru

mC

anad

a, N

R30

pre

gnan

t wom

en

and

39 n

on-p

regn

ant

wom

en

ND

in se

rum

of p

regn

ant w

omen

or

cord

seru

m;

Ari

thm

etic

mea

n, 7

3.6 

ng/L

, (r

ange

, ND

–93.

6 ng

/L) i

n no

n-pr

egna

nt w

omen

No

subj

ect h

ad w

orke

d or

live

d w

ith a

spou

se w

orki

ng in

con

tact

w

ith p

estic

ides

LO

D, 1

5 µg

/L

Ari

s & L

ebla

nc (2

011)

AM

PA, a

min

omet

hylp

hosp

honi

c ac

id; L

OD

, lim

it of

det

ectio

n; N

D, n

ot d

etec

ted;

NR

, not

repo

rted

glyphosate

11

2. Cancer in Humans

2.0 general discussion of epidemiological studies

A general discussion of the epidemiological studies on agents considered in Volume 112 of the IARC Monographs is presented in Section 2.0 of the Monograph on Malathion.

2.1 Cohort studies

See Table 2.1The Agricultural Health Study (AHS), a large

prospective cohort study conducted in Iowa and North Carolina in the USA, is the only cohort study to date to have published findings on expo-sure to glyphosate and the risk of cancer at many different sites (Alavanja et al., 1996; NIH, 2015) (see Section 2.0 of the Monograph on Malathion, in the present volume, for a detailed description of this study).

The enrolment questionnaire from the AHS sought information on the use of 50 pesticides (ever or never exposure), crops grown and live-stock raised, personal protective equipment used, pesticide application methods used, other agri-cultural activities and exposures, nonfarm occup ational exposures, and several lifestyle, medical, and dietary variables. The duration (years) and frequency (days per year) of use was investigated for 22 of the 50 pesticides in the enrolment ques-tionnaire. [Blair et al. (2011) assessed the possible impact of misclassification of occupational pesti-cide exposure on relative risks, demonstrating that nondifferential exposure misclassification biases relative risk estimates towards the null in the AHS and tends to decrease the study power.]

The first report of cancer incidence associated with pesticide use in the AHS cohort considered cancer of the prostate (Alavanja et al., 2003). Risk estimates for exposure to glyphosate were not presented, but no significant exposure–response

association with cancer of the prostate was found. In an updated analysis of the AHS (1993 to 2001), De Roos et al. (2005a) (see below) also found no association between exposure to glyphosate and cancer of the prostate (relative risk, RR, 1.1; 95% CI, 0.9–1.3) and no exposure–response trend (P value for trend = 0.69).

De Roos et al. (2005a) also evaluated associ-ations between exposure to glyphosate and the incidence of cancer at several other sites. The prevalence of ever-use of glyphosate was 75.5% (> 97% of users were men). In this analysis, expo-sure to glyphosate was defined as: (a) ever personally mixed or applied products containing glyphosate; (b) cumulative lifetime days of use, or “cumulative exposure days” (years of use  ×  days/year); and (c) intensity-weighted cumulative exposure days (years of use  ×  days/year  ×  estimated intensity level). Poisson regression was used to estimate exposure–response relations between expo-sure to glyphosate and incidence of all cancers combined, and incidence of 12 cancer types: lung, melanoma, multiple myeloma, and non-Hodgkin lymphoma (see Table 2.1) as well as oral cavity, colon, rectum, pancreas, kidney, bladder, prostate, and leukaemia (results not tabulated). Exposure to glyphosate was not associated with all cancers combined (RR, 1.0; 95% CI, 0.9–1.2; 2088 cases). For multiple myeloma, the relative risk was 1.1 (95% CI, 0.5–2.4; 32 cases) when adjusted for age, but was 2.6 (95% CI, 0.7–9.4) when adjusted for multiple confounders (age, smoking, other pesticides, alcohol consumption, family history of cancer, and education); in analyses by cumu-lative exposure-days and intensity-weighted exposure-days, the relative risks were around 2.0 in the highest tertiles. Furthermore, the associ-ation between multiple myeloma and exposure to glyphosate only appeared within the subgroup for which complete data were available on all the covariates; even without any adjustment, the risk of multiple myeloma associated with glypho-sate use was increased by twofold among the smaller subgroup with available covariate data

IARC MonogRAphs – 112

12

Tabl

e 2.

1 Co

hort

stu

dies

of c

ance

r and

exp

osur

e to

gly

phos

ate

Ref

eren

ce,

stud

y lo

cati

on,

enro

lmen

t pe

riod

/follo

w-

up, s

tudy

-des

ign

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

De

Roos

et a

l. (2

005a

) Io

wa

and

Nor

th

Car

olin

a, U

SA

1993

–200

1

54 3

15 (a

fter e

xclu

sions

, fro

m a

tota

l co

hort

of 5

7 31

1) li

cens

ed p

estic

ide

appl

icat

ors

Expo

sure

ass

essm

ent m

etho

d:

ques

tionn

aire

; sem

i-qua

ntita

tive

asse

ssm

ent f

rom

self-

adm

inis

tere

d qu

estio

nnai

re

Lung

Ever

use

NR

0.9

(0.6

–1.3

)A

ge, s

mok

ing,

ot

her

pest

icid

es,

alco

hol

cons

umpt

ion,

fa

mily

his

tory

of

can

cer,

educ

atio

n

AH

S C

ance

r site

s in

vest

igat

ed: l

ung,

m

elan

oma,

mul

tiple

m

yelo

ma

and

NH

L (r

esul

ts ta

bula

ted)

as

wel

l as o

ral c

avity

, co

lon,

rect

um, p

ancr

eas,

kidn

ey, b

ladd

er, p

rost

ate

and

leuk

aem

ia (r

esul

ts

not t

abul

ated

) [S

tren

gths

: lar

ge c

ohor

t; sp

ecifi

c as

sess

men

t of

gly

phos

ate;

se

miq

uant

itativ

e ex

posu

re a

sses

smen

t. Li

mita

tions

: ris

k es

timat

es b

ased

on

self-

repo

rted

exp

osur

e;

limite

d to

lice

nsed

ap

plic

ator

s; po

tent

ial

expo

sure

to m

ultip

le

pest

icid

es]

Cum

ulat

ive

expo

sure

da

ys:

1–20

401

(ref

.)21

–56

260.

9 (0

.5–1

.5)

57–2

678

260.

7 (0

.4–1

.2)

Tren

d-te

st P

val

ue: 0

.21

Mel

anom

aEv

er u

seN

R1.

6 (0

.8–3

)1–

2023

1 (r

ef.)

21–5

620

1.2

(0.7

–2.3

)57

–267

814

0.9

(0.5

–1.8

)Tr

end-

test

P v

alue

: 0.7

7M

ultip

le

mye

lom

aEv

er u

seN

R2.

6 (0

.7–9

.4)

1–20

81

(ref

.)21

–56

51.

1 (0

.4–3

.5)

Tren

d-te

st P

val

ue: 0

.27

NH

LEv

er u

seN

R1.

1 (0

.7–1

.9)

1–20

291

(ref

.)21

–56

150.

7 (0

.4–1

.4)

57–2

678

170.

9 (0

.5–1

.6)

Tren

d-te

st P

val

ue: 0

.73

glyphosate

13

Ref

eren

ce,

stud

y lo

cati

on,

enro

lmen

t pe

riod

/follo

w-

up, s

tudy

-des

ign

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

Flow

er et

al.

(200

4)

Iow

a an

d N

orth

C

arol

ina,

USA

En

rolm

ent,

1993

–199

7;

follo

w-u

p,

1975

–199

8

21 3

75; c

hild

ren

(age

d

IARC MonogRAphs – 112

14

Ref

eren

ce,

stud

y lo

cati

on,

enro

lmen

t pe

riod

/follo

w-

up, s

tudy

-des

ign

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

And

reot

ti et

al.

(200

9)

Iow

a an

d N

orth

C

arol

ina,

USA

En

rolm

ent,

1993

–199

7;

follo

w-u

p to

20

04

Nes

ted

case

–co

ntro

l stu

dy

Cas

es: 9

3 (r

espo

nse

rate

, NR)

; ide

ntifi

ed

from

pop

ulat

ion-

base

d st

ate-

canc

er

regi

stri

es. I

ncid

ent c

ases

dia

gnos

ed

betw

een

enro

lmen

t and

31

Dec

embe

r 20

04 (>

9 y

ears

follo

w-u

p) in

clud

ed in

th

e an

alys

is. P

artic

ipan

ts w

ith a

ny ty

pe

of p

reva

lent

can

cer a

t enr

olm

ent w

ere

excl

uded

. Vita

l sta

tus w

as o

btai

ned

from

th

e st

ate

deat

h re

gist

ries

and

the

Nat

iona

l D

eath

Inde

x. P

artic

ipan

ts w

ho le

ft N

orth

C

arol

ina

or Io

wa

wer

e no

t sub

sequ

ently

fo

llow

ed fo

r can

cer o

ccur

renc

e. C

ontr

ols:

82 5

03 (r

espo

nse

rate

, NR)

; can

cer-

free

pa

rtic

ipan

ts e

nrol

led

in th

e co

hort

Ex

posu

re a

sses

smen

t met

hod:

qu

estio

nnai

re p

rovi

ding

det

aile

d pe

stic

ide

use,

dem

ogra

phic

and

life

styl

e in

form

atio

n. E

ver-

use

of 2

4 pe

stic

ides

and

in

tens

ity-w

eigh

ted

lifet

ime

days

[(lif

etim

e ex

posu

re d

ays)

× (e

xpos

ure

inte

nsity

sc

ore)

] of 1

3 pe

stic

ides

was

ass

esse

d

Panc

reas

(C

25.0

–C

25.9

)

Ever

ex

posu

re to

gl

ypho

sate

551.

1 (0

.6–1

.7)

Age

, sm

okin

g,

diab

etes

AH

S [S

tren

gths

: lar

ge c

ohor

t. Li

mita

tions

: bas

ed o

n se

lf-re

port

ed e

xpos

ure;

lim

ited

to li

cens

ed

appl

icat

ors;

pote

ntia

l ex

posu

re to

mul

tiple

pe

stic

ides

]

Low

(<

 185

day

s)29

Hig

h

(≥ 1

85 d

ays)

19

Tren

d-te

st P

val

ue: 0

.85

AH

S, A

gric

ultu

ral H

ealth

Stu

dy; N

HL,

non

-Hod

gkin

lym

phom

a; N

R, n

ot re

port

ed

Tabl

e 2.

1 (

cont

inue

d)

glyphosate

15

(De Roos et al., 2005b). [The study had limited power for the analysis of multiple myeloma; there were missing data on covariates when multiple adjustments were done, limiting the interpreta-tion of the findings.] A re-analysis of these data conducted by Sorahan (2015) confirmed that the excess risk of multiple myeloma was present only in the subset with no missing information (of 22 cases in the restricted data set). In a subsequent cross-sectional analysis of 678 male participants from the same cohort, Landgren et al. (2009) did not find an association between exposure to glyphosate and risk of monoclonal gammopathy of undetermined significance (MGUS), a prema-lignant plasma disorder that often precedes multiple myeloma (odds ratio, OR, 0.5; 95% CI, 0.2–1.0; 27 exposed cases).

Flower et al. (2004) reported the results of the analyses of risk of childhood cancer associated with pesticide application by parents in the AHS. The analyses for glyphosate were conducted among 17 357 children of Iowa pesticide appli-cators from the AHS. Parents provided data via questionnaires (1993–1997) and the cancer follow-up (retrospectively and prospectively) was done through the state cancer registries. Fifty incident childhood cancers were identi-fied (1975–1998; age, 0–19 years). For all the children of the pesticide applicators, risk was increased for all childhood cancers combined, for all lymphomas combined, and for Hodgkin lymphoma, compared with the general popula-tion. The odds ratio for use of glyphosate and risk of childhood cancer was 0.61 (95% CI, 0.32–1.16; 13 exposed cases) for maternal use and 0.84 (95% CI, 0.35–2.34; 6 exposed cases) for paternal use. [The Working Group noted that this analysis had limited power to study a rare disease such as childhood cancer.]

Engel et al. (2005) reported on incidence of cancer of the breast among farmers’ wives in the AHS cohort, which included 30 454 women with no history of cancer of the breast before enrol-ment in 1993–1997. Information on pesticide use

and other factors was obtained at enrolment by self-administered questionnaire from the women and their husbands. A total of 309 incident cases of cancer of the breast were identified until 2000. There was no difference in incidence of cancer of the breast for women who reported ever applying pesticides compared with the general popula-tion. The relative risk for cancer of the breast among women who had personally used glypho-sate was 0.9 (95% CI, 0.7–1.1; 82 cases) and 1.3 (95% CI, 0.8–1.9; 109 cases) among women who never used pesticides but whose husband had used glyphosate. [No information on duration of glyphosate use by the husband was presented.] Results for glyphosate were not further stratified by menopausal status.

Lee et al. (2007) investigated the relation-ship between exposure to agricultural pesticides and incidence of cancer of the colorectum in the AHS. A total of 56 813 pesticide applicators with no prior history of cancer of the colorectum were included in this analysis, and 305 incident cancers of the colorectum (colon, 212; rectum, 93) were diagnosed during the study period, 1993–2002. Most of the 50 pesticides studied were not associated with risk of cancer of the colorectum, and the relative risks with expo-sure to glyphosate were 1.2 (95% CI, 0.9–1.6), 1.0 (95% CI, 0.7–1.5), and 1.6 (95% CI, 0.9–2.9) for cancers of the colorectum, colon, and rectum, respectively.

Andreotti et al. (2009) examined associations between the use of pesticides and cancer of the pancreas using a case–control analysis nested in the AHS. This analysis included 93 incident cases of cancer of the pancreas (64 applicators, 29 spouses) and 82 503 cancer-free controls who completed the enrolment questionnaire. Ever-use of 24  pesticides and intensity-weighted life-time days [(lifetime exposure days) × (exposure intensity score)] of 13  pesticides were assessed. Risk estimates were calculated controlling for age, smoking, and diabetes. The odds ratio for ever- versus never-exposure to glyphosate was

IARC MonogRAphs – 112

16

1.1 (95% CI, 0.6–1.7; 55 exposed cases), while the odds ratio for the highest category of level of intensity-weighted lifetime days was 1.2 (95% CI, 0.6–2.6; 19 exposed cases).

Dennis et al. (2010) reported that exposure to glyphosate was not associated with cutaneous melanoma within the AHS. [The authors did not report a risk estimate.]

2.2 Case–control studies on non-hodgkin lymphoma, multiple myeloma, and leukaemia

2.2.1 Non-Hodgkin lymphoma

See Table 2.2

(a) Case–control studies in the midwest USA

Cantor et al. (1992) conducted a case–control study of incident non-Hodgkin lymphoma (NHL) among males in Iowa and Minnesota, USA (see the Monograph on Malathion, Section 2.0, for a detailed description of this study). A total of 622 white men and 1245 population-based controls were interviewed in person. The association with farming occupation and specific agricultural exposures were evaluated. When compared with non-farmers, the odds ratios for NHL were 1.2 (95% CI, 1.0–1.5) for men who had ever farmed, and 1.1 (95% CI, 0.7–1.9; 26 exposed cases; adjusted for vital status, age, state, cigarette smoking status, family history of lymphohaemato poietic cancer, high-risk occupations, and high-risk exposures) for ever handling glyphosate. [There was low power to assess the risk of NHL associ-ated with exposure to glyphosate. There was no adjustment for other pesticides. These data were included in the pooled analysis by De Roos et al. (2003).]

Brown et al. (1993) reported the results of a study to evaluate the association between multiple myeloma and agricultural risk factors in the midwest USA (see the Monograph on

Malathion, Section 2.0, for a detailed description of this study). A population-based case–control study of 173 white men with multiple myeloma and 650 controls was conducted in Iowa, USA, an area with a large farming population. A non-sig-nificantly elevated risk of multiple myeloma was seen among farmers compared with never-farmers. The odds ratio related to exposure to glyphosate was 1.7 (95% CI, 0.8–3.6; 11 exposed cases). [This study had limited power to assess the association between multiple myeloma and exposure to glyphosate. Multiple myeloma is now considered to be a subtype of NHL.]

De Roos et al. (2003) used pooled data from three case–control studies of NHL conducted in the 1980s in Nebraska (Zahm et al., 1990), Kansas (Hoar et al., 1986), and in Iowa and Minnesota (Cantor et al., 1992) (see the Monograph on Malathion, Section 2.0, for a detailed description of these studies) to examine pesticide exposures in farming as risk factors for NHL in men. The study population included 870 cases and 2569 controls; 650 cases and 1933 controls were included for the analysis of 47 pesticides controlling for potential confounding by other pesticides. Both logistic regression and hierarchical regression (adjusted estimates were based on prior distributions for the pesticide effects, which provides more conservative estimates than logistic regression) were used in data analysis, and all models were essentially adjusted for age, study site, and other pesticides. Reported use of glyphosate as well as several individual pesticides was associated with increased incidence of NHL. Based on 36 cases exposed, the odds ratios for the association between exposure to glyphosate and NHL were 2.1 (95% CI, 1.1–4.0) in the logistic regression analyses and 1.6 (95% CI, 0.9–2.8) in the hier-archical regression analysis. [The numbers of cases and controls were lower than those in the pooled analysis by Waddell et al. (2001) because only subjects with no missing data on pesticides were included. The strengths of this study when compared with other studies are that it was large,

glyphosate

17

Tabl

e 2.

2 Ca

se–c

ontr

ol s

tudi

es o

f leu

kaem

ia a

nd ly

mph

oma

and

expo

sure

to g

lyph

osat

e

Ref

eren

ce,

loca

tion

, en

rolm

ent

peri

od

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

USA

Brow

n et

al.

(199

0)

Iow

a an

d M

inne

sota

, USA

19

81–1

983

Cas

es: 5

78 (3

40 li

ving

, 238

de

ceas

ed) (

resp

onse

rate

, 86%

); ca

ncer

regi

stry

or h

ospi

tal

reco

rds

Con

trol

s: 12

45 (8

20 li

ving

, 42

5 de

ceas

ed) (

resp

onse

rate

, 77

–79%

); ra

ndom

-dig

it di

allin

g fo

r tho

se a

ged

< 65

yea

rs a

nd

Med

icar

e fo

r tho

se a

ged

≥ 65

ye

ars

Expo

sure

ass

essm

ent m

etho

d:

ques

tionn

aire

Leuk

aem

iaA

ny

glyp

hosa

te15

0.9

(0.5

–1.6

)A

ge, v

ital s

tatu

s, st

ate,

toba

cco

use,

fa

mily

his

tory

ly

mph

opoi

etic

ca

ncer

, hig

h-ri

sk

occu

patio

ns, h

igh

risk

exp

osur

es

[Str

engt

hs: l

arge

po

pula

tion

base

d st

udy

in a

farm

ing

area

. Li

mita

tions

: not

co

ntro

lled

for

expo

sure

to o

ther

pe

stic

ides

. Lim

ited

pow

er fo

r gly

phos

ate

expo

sure

]

Can

tor e

t al.

(199

2)

Iow

a an

d M

inne

sota

, USA

19

80–1

982

Cas

es: 6

22 (r

espo

nse

rate

, 89.

0%);

Iow

a he

alth

regi

stry

reco

rds

and

Min

neso

ta h

ospi

tal a

nd

path

olog

y re

cord

s C

ontr

ols:

1245

(res

pons

e ra

te,

76–7

9%);

popu

latio

n-ba

sed;

no

can

cer o

f the

lym

pho-

haem

atop

oiet

ic sy

stem

; fr

eque

ncy-

mat

ched

to c

ases

by

age

(5-y

ear g

roup

), vi

tal s

tatu

s, st

ate.

Ran

dom

-dig

it di

allin

g (a

ged

IARC MonogRAphs – 112

18

Ref

eren

ce,

loca

tion

, en

rolm

ent

peri

od

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

Brow

n et

al.

(199

3)

Iow

a, U

SA

1981

–198

4

Cas

es: 1

73 (r

espo

nse

rate

, 84%

); Io

wa

heal

th re

gist

ry

Con

trol

s: 65

0 (r

espo

nse

rate

, 78

%);

Rand

om-d

igit

dial

ling

(age

d <

65 y

ears

) and

Med

icar

e (a

ged

> 65

yea

rs)

Expo

sure

ass

essm

ent m

etho

d:

ques

tionn

aire

Mul

tiple

m

yelo

ma

Any

gl

ypho

sate

111.

7 (0

.8–3

.6)

Age

, vita

l sta

tus

[Str

engt

hs:

popu

latio

n-ba

sed

stud

y. A

reas

with

hig

h pr

eval

ence

of f

arm

ing.

Li

mita

tions

: lim

ited

pow

er fo

r gly

phos

ate

expo

sure

]

De

Roos

et a

l. (2

003)

N

ebra

ska,

Iow

a,

Min

neso

ta,

Kan

sas,

USA

19

79–1

986

Cas

es: 6

50 (r

espo

nse

rate

, 74.

7%);

canc

er re

gist

ries

and

hos

pita

l re

cord

s C

ontr

ols:

1933

(res

pons

e ra

te,

75.2

%);

rand

om-d

igit

dial

ling,

M

edic

are,

stat

e m

orta

lity

files

Ex

posu

re a

sses

smen

t met

hod:

qu

estio

nnai

re; i

nter

view

(dir

ect

or n

ext-

of-k

in)

NH

LA

ny

glyp

hosa

te

expo

sure

362.

1 (1

.1–4

)A

ge, s

tudy

are

a,

othe

r pes

ticid

esBo

th lo

gist

ic

regr

essio

n an

d hi

erar

chic

al re

gres

sion

wer

e us

ed in

dat

a an

alys

is, t

he la

tter

pr

ovid

ing

mor

e co

nser

vativ

e es

timat

es

[Str

engt

hs: i

ncre

ased

po

wer

whe

n co

mpa

red

with

oth

er st

udie

s, po

pula

tion-

base

d, a

nd

cond

ucte

d in

farm

ing

area

s. A

dvan

ced

anal

ytic

al m

etho

ds to

ac

coun

t for

mul

tiple

ex

posu

res]

In

clud

ed p

artic

ipan

ts

from

Can

tor e

t al.

(199

2), Z

ahm

et a

l. (1

990)

, Hoa

r et a

l. (1

986)

, and

Bro

wn

et

al. (

1990

)

Tabl

e 2.

2 (

cont

inue

d)

glyphosate

19

Ref

eren

ce,

loca

tion

, en

rolm

ent

peri

od

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

Lee

et a

l. (2

004a

) Io

wa,

Min

neso

ta

and

Neb

rask

a,

USA

19

80–1

986

Cas

es: 8

72 (r

espo

nse

rate

, NR)

; di

agno

sed

with

NH

L fr

om 1

980

to 1

986

C

ontr

ols:

2381

(res

pons

e ra

te,

NR)

; fre

quen

cy-m

atch

ed

cont

rols

Expo

sure

ass

essm

ent m

etho

d:

ques

tionn

aire

; inf

orm

atio

n on

us

e of

pes

ticid

es a

nd h

isto

ry o

f as

thm

a w

as b

ased

on

inte

rvie

ws

NH

LEx

pose

d to

gl

ypho

sate

–

non-

asth

mat

ics

531.

4 (0

.98–

2.1)

Age

, vita

l sta

tus,

stat

e17

7 pa

rtic

ipan

ts

(45

NH

L ca

ses,

132

cont

rols)

repo

rted

ha

ving

bee

n to

ld b

y th

eir d

octo

r tha

t the

y ha

d as

thm

aEx

pose

d to

gl

ypho

sate

–

asth

mat

ics

61.

2 (0

.4–3

.3)

Can

ada

McD

uffie

et a

l. (2

001)

C

anad

a 19

91–1

994

Cas

es: 5

17 (r

espo

nse

rate

, 67.1

%),

from

can

cer r

egis

trie

s and

ho

spita

ls C

ontr

ols:

1506

(res

pons

e ra

te,

48%

); ra

ndom

sam

ple

from

he

alth

insu

ranc

e an

d vo

ting

reco

rds

Expo

sure

ass

essm

ent

met

hod:

que

stio

nnai

re, s

ome

adm

inis

tere

d by

tele

phon

e, so

me

by p

ost

NH

LEx

pose

d to

gl

ypho

sate

511.

2 (0

.83–

1.74

)A

ge, p

rovi

nce

of

resid

ence

Cro

ss-C

anad

a st

udy

[Str

engt

hs: l

arge

po

pula

tion

base

d st

udy.

Lim

itatio

ns:

no q

uant

itativ

e ex

posu

re d

ata.

Ex

posu

re a

sses

smen

t by

que

stio

nnai

re.

Rela

tivel

y lo

w

part

icip

atio

n]

Une

xpos

ed46

41

> 0

and

≤ 2

days

281.

0 (0

.63–

1.57

)

> 2

days

232.

12 (1

.2–3

.73)

Tabl

e 2.

2 (

cont

inue

d)

IARC MonogRAphs – 112

20

Ref

eren

ce,

loca

tion

, en

rolm

ent

peri

od

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

Kar

unan

ayak

e et

al.

(201

2)

Six

prov

ince

s in

Can

ada

(Que

bec,

Ont

ario

, M

anito

ba,

Sask

atch

ewan

, A

lber

ta, a

nd

Briti

sh C

olum

bia)

19

91–1

994

Inci

dent

cas

es: 3

16 (r

espo

nse

rate

, 68.

4%);

men

age

d ≥

19 y

ears

; as

cert

aine

d fr

om p

rovi

ncia

l ca

ncer

regi

stri

es, e

xcep

t in

Que

bec

(hos

pita

l asc

erta

inm

ent)

Con

trol

s: 15

06 (r

espo

nse

rate

, 48

%);

mat

ched

by

age 

± 2 

year

s to

be

com

para

ble

with

the

age

dist

ribu

tion

of th

e en

tire

case

gr

oup

(HL,

NH

L, M

M, a

nd

STS)

with

in e

ach

prov

ince

of

resid

ence

. Pot

entia

l con

trol

s (m

en a

ged

≥ 19

yea

rs) s

elec

ted

at

rand

om w

ithin

age

con

stra

ints

fr

om th

e pr

ovin

cial

hea

lth

insu

ranc

e re

cord

s (A

lber

ta,

Sask

atch

ewan

, Man

itoba

, Q

uebe

c), c

ompu

teri

zed

tele

phon

e lis

tings

(Ont

ario

), or

vo

ters

’ lis

ts (B

ritis

h C

olum

bia)

Ex

posu

re a

sses

smen

t met

hod:

qu

estio

nnai

re; s

tage

1 u

sed

a se

lf-ad

min

iste

red

post

al

ques

tionn

aire

; and

in st

age

2 de

taile

d pe

stic

ide

expo

sure

in

form

atio

n w

as c

olle

cted

by

tele

phon

e in

terv

iew

HL

(IC

DO

2 in

clud

ed

nodu

lar

scle

rosi

s (M

9656

/3;

M96

63/3

; M

9664

/3;

M96

65/3

; M

9666

/3;

M96

67/3

), ly

mph

ocyt

ic

pred

omin

ance

(M

9651

/3;

M96

57/3

; M

9658

/3;

M96

59/3

), m

ixed

ce

llula

rity

(M

9652

/3),

lym

phoc

ytic

de

plet

ion

(M96

53/3

; M

9654

/3),

mis

cella

neou

s (o

ther

M

9650

-M96

69

code

s for

HL)

Gly

phos

ate-

base

d fo

rmul

atio

n

381.1

4 (0

.74–1

.76)

Age

gro

up,

prov

ince

of

resid

ence

Cro

ss C

anad

a st

udy

Base

d on

the

stat

istic

al

anal

ysis

of p

ilot s

tudy

da

ta, i

t was

dec

ided

th

at th

e m

ost e

ffici

ent

defin

ition

of p

estic

ide

expo

sure

was

a

cum

ulat

ive

expo

sure

≥ 

10 h

ours

/yea

r to

any

com

bina

tion

of p

estic

ides

. This

disc

rim

inat

ed (a

) be

twee

n in

cide

ntal

, by

stan

der,

and

envi

ronm

enta

l ex

posu

re v

s mor

e in

tens

ive

expo

sure

, an

d (b

) bet

wee

n ca

ses

and

cont

rols

[Str

engt

hs: l

arge

stud

y. Li

mita

tions

: low

re

spon

se ra

tes]

Gly

phos

ate-

base

d fo

rmul

atio

n

380.

99 (0

.62–

1.56

)A

ge g

roup

, pr

ovin

ce o

f re

siden

ce, m

edic

al

hist

ory

Tabl

e 2.

2 (

cont

inue

d)

glyphosate

21

Ref

eren

ce,

loca

tion

, en

rolm

ent

peri

od

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

Kac

huri

et a

l. (2

013)

Si

x C

anad

ian

prov

ince

s (Br

itish

C

olum

bia,

A

lber

ta,

Sask

atch

ewan

, M

anito

ba,

Ont

ario

and

Q

uebe

c)

1991

–199

4

Cas

es: 3

42 (r

espo

nse

rate

, 58%

); m

en a

ged

≥ 19

yea

rs d

iagn

osed

be

twee

n 19

91 a

nd 1

994

wer

e as

cert

aine

d fr

om p

rovi

ncia

l ca

ncer

regi

stri

es e

xcep

t in

Que

bec,

whe

re a

scer

tain

ed fr

om

hosp

itals

Con

trol

s: 13

57 (r

espo

nse

rate

, 48

%);

men

age

d ≥

19 y

ears

se

lect

ed ra

ndom

ly u

sing

pr

ovin

cial

hea

lth in

sura

nce

reco

rds,

rand

om d

igit

dial

ling,

or

vot

ers’

lists

, fre

quen

cy-

mat

ched

to c

ases

by

age

(±2 

year

s) a

nd p

rovi

nce

of

resid

ence

Ex

posu

re a

sses

smen

t met

hod:

qu

estio

nnai

re

Mul

tiple

m

yelo

ma

Gly

phos

ate

use

321.1

9 (0

.76–

1.87

)A

ge, p

rovi

nce

of

resid

ence

, use

of a

pr

oxy

resp

onde

nt,

smok

ing

stat

us,

med

ical

var

iabl

es,

fam

ily h

isto

ry o

f ca

ncer

Cro

ss-C

anad

a st

udy

[Str

engt

hs:

popu

latio

n-ba

sed

case

–con

trol

stud

y. Li

mita

tions

: rel

ativ

ely

low

resp

onse

rate

s]

Use

of

glyp

hosa

te

(> 0

and

≤ 

2 da

ys p

er

year

)

150.

72 (0

.39–

1.32

)

Use

of

glyp

hosa

te

(> 2

 day

s per

ye

ar)

122.

04 (0

.98–

4.23

)

Swed

enN

ords

tröm

et a

l. (1

998)

Sw

eden

19

87–1

992

Cas

es: 1

11 (r

espo

nse

rate

, 91%

); 12

1 H

CL

case

s in

men

iden

tified

fr

om S

wed

ish

canc

er re

gist

ry

Con

trol

s: 40

0 (r

espo

nse

rate

, 83

%);

484

(four

con

trol

s/ca

se)

mat

ched

for a

ge a

nd c

ount

y;

natio

nal p

opul

atio

n re

gist

ry

Expo

sure

ass

essm

ent m

etho

d:

ques

tionn

aire

; con

sider

ed

expo

sed

if m

inim

um e

xpos

ure

of 1

wor

king

day

(8 h

) and

an

indu

ctio

n pe

riod

of a

t lea

st

1 ye

ar

HC

LEx

pose

d to

gl

ypho

sate

43.

1 (0

.8–1

2)A

geO

verla

ps w

ith H

arde

ll et

al.

(200

2). H

CL

is a

su

btyp

e of

NH

L [S

tren

gths

: po

pula

tion-

base

d ca

se–c

ontr

ol st

udy.

Lim

itatio

ns: L

imite

d po

wer

. Ther

e w

as n

o ad

just

men

t for

oth

er

expo

sure

s]

Tabl

e 2.

2 (

cont

inue

d)

IARC MonogRAphs – 112

22

Ref

eren

ce,

loca

tion

, en

rolm

ent

peri

od

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

Har

dell

&

Erik

sson

(199

9)

Nor

ther

n an

d m

iddl

e Sw

eden

19

87–1

990

Cas

es: 4

04 (1

92 d

ecea

sed)

(r

espo

nse

rate

, 91%

); re

gion

al

canc

er re

gist

ries

C

ontr

ols:

741

(res

pons

e ra

te,

84%

); liv

e co

ntro

ls m

atch

ed fo

r ag

e an

d co

unty

wer

e re

crui

ted

from

the

natio

nal p

opul

atio

n re

gist

ry, a

nd d

ecea

sed

case

s m

atch

ed fo

r age

and

yea

r of

deat

h w

ere

iden

tified

from

the

natio

nal r

egis

try

for c

ause

s of

deat

h Ex

posu

re a

sses

smen

t met

hod:

qu

estio

nnai

re

NH

L (I

CD

-9

200

and

202)

Ever

gl

ypho

sate

–

univ

aria

te

42.

3 (0

.4–1

3)N

ot sp

ecifi

ed in

th

e m

ultiv

aria

ble

anal

ysis

Ove

rlaps

with

Har

dell

et a

l. (2

002)

[S

tren

gths

: po

pula

tion-

base

d st

udy.

Lim

itatio

ns: f

ew

subj

ects

wer

e ex

pose

d to

gly

phos

ate

and

the

stud

y ha

d lim

ited

pow

er. A

naly

ses w

ere

“mul

tivar

iate

” but

co

vari

ates

wer

e no

t sp

ecifi

ed]

Ever

gl

ypho

sate

–

mul

tivar

iate

NR

5.8

(0.6

–54)

Har

dell

et a

l. (2

002)

Sw

eden

; fou

r N

orth

ern

coun

ties a

nd

thre

e co

untie

s in

mid

Sw

eden

19

87–1

992

Cas

es: 5

15 (r

espo

nse

rate

, 91%

in

bot

h st

udie

s); S

wed

ish

canc

er

regi

stry

C

ontr

ols:

1141

(res

pons

e ra

tes,

84%

and

83%

%);

natio

nal

popu

latio

n re

gist

ry

Expo

sure

ass

essm

ent m

etho

d:

ques

tionn

aire

NH

L an

d H

CL

Ever

gl

ypho

sate

ex

posu

re

(uni

vari

ate)

83.

04 (1

.08–

8.5)

Age

, cou

nty,

stud

y sit

e, v

ital s

tatu

s, ot

her p

estic

ides

in

the

mul

tivar

iate

an

alys

is

Ove

rlaps

with

N

ords

tröm

et a

l. (1

998)

and

Har

dell

&

Erik

sson

(199

9),

[Str

engt

hs: l

arge

po

pula

tion-

base

d st

udy.

Lim

itatio

ns:

limite

d po

wer

for

glyp

hosa

te e

xpos

ure]

Ever

gl

ypho

sate

ex

posu

re

(mul

tivar

iate

)

81.

85 (0

.55–

6.2)

Tabl

e 2.

2 (

cont

inue

d)

glyphosate

23

Ref

eren

ce,

loca

tion

, en

rolm

ent

peri

od

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

Erik

sson

et a

l. (2

008)

Sw

eden

. Fou

r he

alth

serv

ice

area

s (Lu

nd,

Link

opin

g,

Ore

bro

and

Um

ea)

1999

–200

2

Cas

es: 9

10 (r

espo

nse

rate

, 91

%);

inci

dent

NH

L ca

ses

wer

e en

rolle

d fr

om u

nive

rsity

ho

spita

ls C

ontr

ols:

1016

(res

pons

e ra

te,

92%

); na

tiona

l pop

ulat

ion

regi

stry

Ex

posu

re a

sses

smen

t met

hod:

qu

estio

nnai

re

NH

LA

ny

glyp

hosa

te

292.

02 (1

.1–3

.71)

Age

, sex

, yea

r of

enro

lmen

t[S

tren

gths

: po

pula

tion-

base

d ca

se-c

ontr

ol.

Lim

itatio

ns: l

imite

d po

wer

for g

lyph

osat

e]

Any

gl

ypho

sate

* 29

1.51

(0.7

7–2.

94)

* Exp

osur

e to

oth

er

pest

icid

es (e

.g. M

PCA

) co

ntro

lled

in th

e an

alys

is

≤ 10

day

s per

ye

ar u

se12

1.69

(0.7

–4.0

7)

> 10

day

s per

ye

ar u

se17

2.36

(1.0

4–5.

37)

NH

L1–

10 y

rsN

R1.1

1 (0

.24–

5.08

)> 

10 y

rsN

R2.

26 (1

.16–4

.4)

B-ce

ll ly

mph

oma

Expo

sure

to

glyp

hosa

teN

R1.8

7 (0.9

98–3

.51)

Lym

phoc

ytic

ly

mph

oma/

B-C

LL

Expo

sure

to

glyp

hosa

teN

R3.

35 (1

.42–

7.89)

Diff

use

larg

e B-

cell

lym

phom

a

Expo

sure

to

glyp

hosa

teN

R1.

22 (0

.44–

3.35

)

Folli

cula

r, gr

ade

I–II

IEx

posu

re to

gl

ypho

sate

NR

1.89

(0.6

2–5.

79)

Oth

er

spec

ified

B-c

ell

lym

phom

a

Expo

sure

to

glyp

hosa

teN

R1.6

3 (0.

53–4

.96)

Uns

peci

fied

B-ce

ll ly

mph

oma

Expo

sure

to

glyp

hosa

teN

R1.4

7 (0

.33–

6.61

)

T-ce

ll ly

mph

oma

Expo

sure

to

glyp

hosa

teN

R2.

29 (0

.51–

10.4

)

Uns

peci

fied

NH

LEx

posu

re to

gl

ypho

sate

NR

5.63

(1.4

4–22

)

Tabl

e 2.

2 (

cont

inue

d)

IARC MonogRAphs – 112

24

Ref

eren

ce,

loca

tion

, en

rolm

ent

peri

od

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

Oth

er st

udie

s in

Euro

peO

rsi e

t al.

(200

9)

Fran

ce

2000

–200

4

Cas

es: 4

91 (r

espo

nse

rate

, 95.

7%);

case

s (24

4 N

HL;

87

HL;

104

LP

Ss; 5

6 M

M) w

ere

recr

uite

d fr

om m

ain

hosp

itals

of th

e Fr

ench

citi

es o

f Bre

st, C

aen,

N

ante

s, Li

lle, T

oulo

use

and

Bord

eaux

, age

d 20

–75

year

s; A

LL

case

s exc

lude

d C

ontr

ols:

456

(res

pons

e ra

te,

91.2

%);

mat

ched

on

age

and

sex,

re

crui

ted

in th

e sam

e hos

pita

ls as

th

e ca

ses,

mai

nly

in o

rtho

paed

ic

and

rheu

mat

olog

ical

de

part

men

ts a

nd re

sidin

g in

the

hosp

ital’s

cat

chm

ent a

rea

Expo

sure

ass

essm

ent m

etho

d:

ques

tionn

aire

NH

LA

ny

glyp

hosa

te

expo

sure

121.

0 (0

.5–2

.2)

Age

, cen

tre,

so

cioe

cono

mic

ca

tego

ry (b

lue/

whi

te c

olla

r)

[Lim

itatio

ns: l

imite

d po

wer

for g

lyph

osat

e]

HL

Any

exp

osur

e to

gly

phos

ate

61.

7 (0

.6–5

)

LPS

Any

exp

osur

e to

gly

phos

ate

40.

6 (0

.2–2

.1)

MM

Any

exp

osur

e to

gly

phos

ate

52.

4 (0

.8–7

.3)

All

lym

phoi

d ne

opla

sms

Any

exp

osur

e to

gly

phos

ate

271.

2 (0

.6–2

.1)

NH

L, d

iffus

e la

rge

cell

lym

phom

a

Occ

upat

iona

l us

e of

gl

ypho

sate

51.

0 (0

.3–2

.7)

NH

L, fo

llicu

lar

lym

phom

aO

ccup

atio

nal

expo

sure

to

glyp

hosa

te

31.

4 (0

.4–5

.2)

LPS/

CLL

Occ

upat

iona

l ex

posu

re to

gl

ypho

sate

20.

4 (0

.1–1

.8)

LPS/

HC

LO

ccup

atio

nal

expo

sure

to

glyp

hosa

te

21.

8 (0

.3–9

.3)

Tabl

e 2.

2 (

cont

inue

d)

glyphosate

25

Ref

eren

ce,

loca

tion

, en

rolm

ent

peri

od

Popu

lati

on si

ze, d

escr

ipti

on,

expo

sure

ass

essm

ent m

etho

dO

rgan

site

(I

CD

cod

e)Ex

posu

re

cate

gory

or

leve

l

Expo

sed

case

s/

deat

hs

Ris

k es

tim

ate

(95%

CI)

Cov

aria

tes

cont

rolle

dC

omm

ents

Coc

co et

al.

(201

3)C

zech

Rep

ublic

, Fr

ance

, Ger

man

y, It

aly,

Irel

and

and

Spai

n19

98–2

004

Cas

es: 2

348

(res

pons

e ra

te, 8

8%);

case

s wer

e al

l con

secu

tive

adul

t pa

tient

s firs

t dia

gnos

ed w

ith

lym

phom

a du

ring

the

stud

y pe

riod

, res

iden

t in

the

refe

rral

ar

ea o

f the

par

ticip

atin

g ce

ntre

sC

ontr

ols:

2462

(res

pons

e ra

te,

81%

hos

pita

l; 52

% p

opul

atio

n);

cont

rols

from

Ger

man

y an

d It

aly

wer

e ra

ndom

ly se

lect

ed

by sa

mpl

ing

from

the

gene

ral

popu

latio

n an

d m

atch

ed to

cas

es

on se

x, 5

-yea

r age

-gro

up, a

nd

resid

ence

are

a. Th

e re

st o

f the

ce

ntre

s use

d m

atch

ed h

ospi

tal

cont

rols

, exc

ludi

ng d

iagn

oses

of

canc

er, i

nfec

tious

dis

ease

s and

im

mun

odefi

cien

cy d

isea

ses

Expo

sure

ass

essm

ent m

etho

d:

ques

tionn

aire

; sup

port

of a

cro

p-ex

posu

re m

atri

x to

supp

lem

ent

the

avai

labl

e in

form

atio

n,

indu

stri

al h

ygie

nist

s and

oc

cupa

tiona

l exp

erts

in e

ach

part

icip

atin

g ce

ntre

revi

ewed

the

gene

ral q

uest

ionn

aire

s and

job

mod

ules

to a

sses

s exp

osur

e to

pe

stic

ides

B-ce

ll ly

mph

oma

Occ

upat

iona

l ex

posu

re to

gl

ypho

sate

43.

1 (0

.6–1

7.1)

Age

, sex

, ed

ucat

ion,

cen

tre

EPIL

YM

PH c

ase-

cont

rol s

tudy

in si

x Eu

rope

an c

ount

ries

ALL

, acu

te ly

mph

ocyt

ic le

ukae

mia

; B-C

LL, c

hron

ic ly

mph

ocyt

ic le

ukae

mia

; CL