2,4-dichlorophenoxyacetic...
TRANSCRIPT
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1
1. Exposure Data
1.1 Identification of the agent
1.1.1 Nomenclature
Chem. Abstr. Serv. Reg. No.: 94-75-7Chem. Abstr. Serv. Name: 2,4-Dichlorophenoxy-acetic acidPreferred IUPAC Name: 2-(2,4-Dichloro-phenoxy) acetic acidSynonyms: 2,4-D; 2,4 dichlorophenoxyacetic acid; 2,4-dichlorophenoxyacetic acidTrade Names: 2,4-Dichlorophenoxyacetic acid (2,4-D) has been used in many commer-cial product formulations. Selected trade names include: Hedonal; 2,4-D; Estone; Agrotect; Fernesta; Fernimine; Netagrone; Tributon; Vergemaster; Amoxone; Dicopur; Dormone; Ipaner; Moxone; Phenox; Pielik; Rhodia; Weedone; B-Selektonon.
Additional trade names are available in the PubChem Compound database (NCBI, 2015).
1.1.2 Structural and molecular formulae, and relative molecular mass
Cl
Cl OOH
O
Molecular formula: C8H6Cl2O3Relative molecular mass: 221.03
1.1.3 Chemical and physical properties of the pure substance
Description: Colourless crystals or white powderSolubility: Slightly soluble in water (g/100 mL at 25 °C, 0.031). Soluble in organic solvents (ethanol, acetone, dioxane)Octanol/water partition coefficient: log Pow, 2.81Conversion factor: 1 ppm = 9.04 mg/m3, assuming normal temperature (25 °C) and pressure (101 kPa)
See IPCS/ICSC (2015)
2,4-Dichlorophenoxyacetic aciD
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IARC MonogRAphs – 113
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1.1.4 Esters and salts of 2,4-D
Several esters and salts of 2,4-D with various properties have been manufactured and used in herbicide products (NPIC, 2008). In humans, esters and salts of 2,4-D undergo rapid acid or enzymatic hydrolysis in vivo to yield 2,4-D (Garabrant & Philbert, 2002) (see Section 4.1). Esters and salts also undergo hydrolysis to the acid in environmental media at different rates depending on specific conditions of pH, moisture, and other factors (NPIC, 2008). Relevant ester and salt forms of 2,4-D include the following:
• 2,4-D salt (CAS No. 2702-72-9)• 2,4-D diethanolamine salt (CAS No.
5742-19-8)• 2,4-D dimethylamine salt (CAS No.
2008-39-1)• 2,4-D isopropylamine salt (CAS No.
5742-17-6)• 2,4-D isopropanolamine salt (CAS No.
32341-80-3)• 2,4-D butoxyethyl ester (CAS No. 1929-73-3)• 2,4-D butyl ester (CAS No. 94-80-4)• 2,4-D 2-ethylhexyl ester (CAS No. 1928-43-4)
• 2,4-D isopropyl ester (CAS No. 94-11-1)• 2,4-D isooctyl ester (CAS No. 25168-26-7)• 2,4-D choline salt (CAS No. 1048373-72-3)
Physical properties of these 2,4-D salts and esters have been reported elsewhere (NPIC, 2008).
1.2 production and use
1.2.1 Production
Two processes are currently used for the production of 2,4-D. In the first process, phenol is condensed with chloroacetic acid forming phenoxyacetic acid, which is subsequently chlo-rinated (Fig. 1.1). In the second process, phenol is chlorinated, generating 2,4-dichlorophenol, which is subsequently condensed with chloro-acetic acid (Fig. 1.2).
The butyl ester derivative of 2,4-D is produced by the esterification of the acid with butanol in the presence of a ferric chloride catalyst and chlorine (Liu et al., 2013).
No reliable data on current global production of 2,4-D were available to the Working Group.
Fig. 1.1 production of 2,4-dichlorophenoxyacetic acid (2,4-D) via 2,4-dichlorophenol
OH OH
Cl
Cl
Cl2
2,4-Dichlorophenol
Phenol
Chloroacetic acid
OCH2COOH
Cl
Cl
2,4-Dichlorophenoxyacetic acid
COOHCH2Cl
Reprinted from Chemosphere, 92(3), Liu et al. (2013) Formation and contamination of polychlorinated dibenzodioxins/dibenzofurans (PCDD/Fs), polychlorinated biphenyls( PCBs), pentachlorobenzene (PeCBz), hexachlorobenzene (HxCBz), and polychlorophenols in the production of 2,4-D products, pp 304–308, Copyright (2013), with permission from Elsevier
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2,4-Dichlorophenoxyacetic acid
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In 2010, the production of 2,4-D reached 40 000 tonnes in China (Liu et al., 2013).
1.2.2 Use
2,4-D is a synthetic auxin, and was the first chemical that could selectively control dicot-yledons or broadleaf plants, but spare most monocotyledons, which include grasses and narrow-leaf crops such as wheat, maize (corn), rice, and similar cereal crops (Song, 2014).
2,4-D was first marketed in 1944 and produced by the American Chemical Paint Company. The derivatives of 2,4-D constitute a series of system-atic herbicides that are widely used in broad-leaved weeds. 2,4-D is one of the world’s most common herbicides because of its general appli-cability and low cost (Liu et al., 2013)
There are more than 600 products containing 2,4-D currently on the market (Song, 2014). In 2001, the dimethylamine salt and 2-ethylhexyl ester accounted for approximately 90–95% of the total global use of 2,4-D (Charles et al., 2001).
2,4-D is sold in various formulations under a wide variety of brand names and is found, for example, in commercial mixtures of lawn herbicide. 2,4-D can be used alone and is also
commonly formulated with other herbicides, for example, dicamba (3,6-dichloro-2-meth-oxybenzoic acid), mecoprop (methylchloro-phenoxypropionic acid, MCPP), mecoprop-P (the (R)-(+)-enantiomer of mecoprop), MCPA (2-methyl-4-chlorophenoxyacetic acid), picloram (4-amino-3,5,6 trichloropicolinic acid), and clopyralid (3,6-dichloro pyridine-2-carboxylic acid) (PubChem, 2015). 2,4-D in combination with glyphosate is used as the basis of a herbicide formulation designed for weed control in crops of corn and soybean that have been genetically modified to tolerate 2,4-D and glyphosate via insertion of a bacterial aryloxyalkanoate dioxy-genase gene into the plant genome (Wright et al., 2010).
On 18 September 2014, the United States Environmental Protection Agency (EPA) granted registration for a herbicide containing the active ingredients 2,4-D, choline salt, and glyphosate dimethylammonium salt to be used on corn and soybean crops genetically engineered to be resistant to 2,4-D and glyphosate (EPA, 2014).
In the USA, 2,4-D is one of the 10 most commonly used conventional active ingredients of pesticide used in the agricultural sector. Use estimates from 2001 to 2007 ranged from 24 to
Fig. 1.2 production of 2,4-dichlorophenoxyacetic acid (2,4-D) via phenoxyacetic acid
OH
Chloroacetic acid
OCH2COOH OCH2COOH
Cl
Cl
Cl2
Phenoxyacetic acid 2,4-Dichlorophenoxyacetic acid
Phenol
COOHCH2
Cl
Reprinted from Chemosphere, 92(3), Liu et al. (2013) Formation and contamination of polychlorinated dibenzodioxins/dibenzofurans (PCDD/Fs), polychlorinated biphenyls( PCBs), pentachlorobenzene (PeCBz), hexachlorobenzene (HxCBz), and polychlorophenols in the production of 2,4-D products, pp 304–308, Copyright (2013), with permission from Elsevier
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IARC MonogRAphs – 113
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35 million pounds [~11 × 103 to 16 × 103 tonnes]. In the non-agricultural sectors, i.e. home/garden and industry/commercial/government, 2,4-D is the most commonly used active herbicide ingre-dient, with use estimates between 2001 and 2007 of 8–11 and 16–22 million pounds [~3.6 × 103 to 5 × 103 and 7 × 103 to 10 × 103 tonnes], respect-ively (EPA, 2011). In Canada, 14 tonnes and 87 tonnes of 2,4-D (diverse formulations) were used in British Columbia, and in Ontario respectively, in 2003 (CAREX-CANADA, 2009).
In the USA, application of the herbicide has occurred in pasture and rangelands (24%), lawns by homeowners with fertilizer (12%), spring wheat (8%), winter wheat (7%), lawn/garden without fertilizer (6%), soybean (4%), summer fallow (3%), hay other than alfalfa (3%) and road-ways (3%). Other crops on which 2,4-D is used included filberts, sugarcane, barley, seed crops, apples, rye, cherries, oats, millet, rice, soybean, and pears. 2,4-D is also used in forestry, turf-grass management, and in the control of weeds near powerlines, railways, and similar corridors. Rates of application were generally less than 1.7 kg of acid equivalents per hectare, and gener-ally less than 2.2 kg/Ha were applied annually. 2,4-D is predominantly used in the Midwest, Great Plains and Northwestern regions of the USA (EPA, 2005). Low concentrations of 2,4-D are used as plant growth regulators to induce callus formation (Liu et al., 2013). Agricultural use of 2,4-D includes both crop and non-crop applications of primarily liquid formulations, and a variety of application methods ranging from tractor-mounted booms to backpack sprayers. Forestry application ranges from back-pack spraying to aerial application. Turf appli-cations may use either liquid spray or granular formulations.
A mixture of roughly equal parts of 2,4-D and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), known as “agent orange”, was used by military forces of the USA as a defoliant in the Viet Nam war (Kahn et al., 1988).
1.3 Measurement and analysis
Exposure to humans may occur as a result of ingestion, inhalation, or dermal absorption of 2,4-D, or any of its salts and esters, through occupational exposure during manufacture or use of herbicide products, or via contact with 2,4-D residues in food, water, air, or soil. Measurement methods have been developed for analysis of 2,4-D and its esters and salts in a wide range of biological, personal air, and dermal samples taken during monitoring for expo-sure, and in food, and environmental media. Some gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods have been developed as “multi-residue” methods that can provide simultaneous extraction and anal-ysis of other phenoxy acid herbicides (e.g. MCPA, MCPP, dicamba, 2,4,5-T) or even wider ranges of acidic or otherwise difficult-to-analyse pesticides (Raina-Fulton, 2014).
Analysis of 2,4-D acid in urine is the most widely used approach for biomonitoring of human exposure (Baker et al., 2000; Lindh et al., 2008), because excretion of 2,4-D and its acid-hy-drolysable conjugates is almost exclusively in the urine. Esters and salts of 2,4-D are rapidly hydro-lysed to the acid in exposed humans (see Section 4.1). This is particularly relevant in occupational settings, where exposure to the ester and salt forms are likely to occur. Methods for analysis of 2,4-D in other biological media, including blood and milk, have been developed and applied primarily in studies of toxicology and metabo-lism in experimental animals (Dickow et al., 2001; Stürtz et al., 2006). Methods of measure-ment of exposure for 2,4-D acid and its salt and ester forms have included personal and area air samples, dermal patch and bodysuit samples, and hand-wipe samples that are most often used for assessing occupational exposures (NIOSH, 1994; Gardner et al., 2005). Methods for analysis of 2,4-D in air (Waite et al., 2005), water (EPA,
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2,4-Dichlorophenoxyacetic acid
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2000; McManus et al., 2014), soil (Schaner et al., 2007), house dust (Colt et al., 2008), and food (Morgan et al., 2004; Santilio et al., 2011; Shida et al., 2015), have primarily (but not exclusively) focused on the acid form of 2,4-D, partly because ester and amine salts of 2,4-D are hydrolysed to the acid at different rates in environmental media, depending on oxygen availability, moisture, and pH levels. In water and aerobic soil and sediment, the half-lives of esters and amines are shorter (in the order of days) than in anaerobic media. 2,4-D undergoes degradation in the outdoor environ-ment, with potentially slower degradation rates in indoor environments (Walters, 1999). Examples of methods of analysis for 2,4-D in a range of media are listed in Table 1.1.
1.4 occurrence and exposure
2,4-D and its salts and esters do not occur naturally in the environment. Due to wide-spread production and use of herbicide products containing 2,4-D, there is considerable poten-tial for exposure of humans in occupational and non-occupational settings, as illustrated in Fig 1.3 and Fig. 1.4.
Most of the available data on exposure and environmental occurrence were from North America and Europe. Fewer data were available from other regions of the world. Given the wide-spread global use of 2,4-D, the lack of data should not be taken as an indicator that human expo-sures do not occur in other regions.
table 1.1 representative methods for the analysis of 2,4-D
Sample matrix Assay procedure Limit of detection Reference
Air, workplace HPLC-UV 15 µg per filter NIOSH (1994)Air, ambient GC-MSD 0.005 ng/m3 based on a 2000 m3 sample volume Waite et al. (2005)Ground water UHPLC-MS/MS 0.0003 µg/L; LOQ, 0.0005 µg/L for 500 mL water samples McManus et al. (2014)Drinking-water GC-ECD 0.055 µg/L EPA (2000)Soil LC-MS/MS Reporting limit, 0.010 ppm for 20 g of soil sample Schaner et al. (2007)Personal exposure (air, hand-wipe, dermal patch)
LC-MS/MS MDL, 1.1–2.9 μg/L Gardner et al. (2005)
Urine (human) LC-MS/MS 0.05 µg/L Lindh et al. (2008)Urine (human) HPLC-MS/MS 0.29 µg/L Baker et al. (2000)Plasma (dog) HPLC-FD LOQ, 500 µg/L Dickow et al. (2001)Serum and milk (rat) GC-ECD 0.02 ppm [180 µg/L] Stürtz et al. (2006)Fruits and vegetables LC-MS/MS LOD, not reported; recovery tests performed at
0.01 mg/kgShida et al. (2015)
Cereals LC-MS/MS LOQ, 0.05 mg/kg Santilio et al. (2011)Food (duplicate diet) GC-MS MDL, 0.25 ng/g for solid food based on 8 g of
homogenized food MDL, 0.20 ng/mL for liquid food based on 30 mL homogenized liquid food
Morgan et al. (2004)
House dust GC-MS MDL, 5 ng/g for 0.5 g of dust sample Colt et al. (2008)2,4-D, 2,4-dichlorophenoxyacetic acid; ECD, electron capture detector; FD, fluorescence detection; GC, gas chromatography; HPLC, high-performance liquid chromatography; LC, liquid chromatography; LOD, limit of detection; LOQ, limit of quantitation; MDL, method detection limit; MS, mass spectrometry; MS/MS, tandem mass spectrometry; MSD, mass-selective detection; UHPLC, ultra-high performance liquid chromatography
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1.4.1 Occupational exposure
Occupational exposure to 2,4-D can result from product manufacturing, agricultural use, forestry, right-of-way, and turf/lawn applica-tions. Indirect or para-occupational exposure may occur in some populations as a result of “take-home” and “drift” pathways. Occupational exposure to 2,4-D typically occurs as a result of dermal absorption and inhalation, although some incidental ingestion may also occur. Some studies cited in a review of dermal absorption of 2,4-D in humans showed that dermal exposure is
the primary route of exposure for herbicide-spray applicators (Ross et al., 2005).
(a) Manufacture
In two studies of occupational exposure, workers involved in manufacturing prod-ucts containing 2,4-D had urinary biomarker concentrations ranging from 35 to 12 693 µg/L, with a mean of 1366 µg/L, in one study as shown in Table 1.2 (Vural & Burgaz, 1984; Knopp, 1994). In one of these studies, values for room air and personal air were 3.2–245 µg/m3 and
Fig. 1.3 Urinary concentrations of 2,4-dichlorophenoxyacetic acid (2,4-D)(mean, median, or geometric mean) from studies of occupational or para-occupational exposure, and in the general population
Compiled by the Working GroupIncludes multiple subsets of results from several studies: Kolmodin-Hedman & Erne (1980), Draper (1982), Libich et al. (1984), Vural & Burgaz (1984), Knopp (1994), Garry et al. (2001), Hines et al. (2001), Arbuckle et al. (2004, 2005), Curwin et al. (2005a), Alexander et al. (2007), Arcury et al. (2007), Morgan et al. (2008), Bhatti et al. (2010), Thomas et al. (2010a), Zhang et al. (2011), Jurewicz et al. (2012), Rodríguez et al. (2012), Raymer et al. (2014), and CDC (2015)d, day; occ., occupational
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2,4-Dichlorophenoxyacetic acid
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23.4–495 µg/m3, respectively (Vural & Burgaz, 1984).
(b) Application
Many studies have been conducted to measure occupational exposure to 2,4-D from agricul-ture, forestry, right-of-way, and turf application of herbicidal products (Table 1.2). Both external (dermal, air) and biomonitoring methods have been used for exposure assessment of the appli-cator. Urinary 2,4-D concentrations for forestry applicators ranged from below the limit of detec-tion (LOD) to 1700 µg/L, with means ranging from 17.6 to 454 µg/L for different job tasks (Garry et al., 2001). Estimated mean values for urinary excretion or the absorbed dose ranged from 2.7
to 98 µg/kg bw per day across several studies of forestry-related job tasks (Lavy et al., 1982; Lavy et al., 1987; Zhang et al., 2011). Professional agricultural applicators had urinary concen-trations of 2,4-D ranging from not detected (ND) to 2858 µg/L, with values of 58 (geometric mean, GM) and 94 (median) µg/L (Hines et al., 2003; Bhatti et al., 2010). Many studies reported urinary results for farmer applicators, with 2,4-D concentrations ranging from ND to 14 000 µg/L, with GM values ranging from 5.8 to 715 µg/L, and a mean value of 8000 µg/L reported in one study (Kolmodin-Hedman & Erne, 1980; Draper & Street, 1982; Vural & Burgaz, 1984; Grover et al., 1986; Arbuckle et al., 2005; Curwin et al., 2005a; Alexander et al., 2007; Thomas et al.,
Fig. 1.4 estimated exposure to 2,4-dichlorophenoxyacetic acid (2,4-D) from studies of occupational or para-occupational exposure, and in the general population
Compiled by the Working GroupEstimates were based on urinary concentrations, except for the general population, for which estimates were derived from residential and dietary measurements. Includes multiple subsets of results from several studies: Lavy et al. (1987), Hines et al. (2001), Alexander et al. (2007), Thomas et al. (2010a), Wilson et al. (2010), Zhang et al. (2011), and Morgan et al. (2014)
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IARC MonogRAphs – 113
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tabl
e 1.
2 o
ccup
atio
nal e
xpos
ure
to 2
,4-D
Cou
ntry
, ye
arJo
b/pr
oces
sM
edia
No.
of
expo
sed
indi
vidu
als
Res
ults
Com
men
ts/a
ddit
iona
l dat
aR
efer
ence
Mea
nR
ange
Her
bici
de p
rodu
ctio
nG
erm
any,
1985
–89
2,4-
D
herb
icid
e pr
oduc
tion
Uri
ne41
–35
–12
963
µg/L
Kno
pp (1
994)
Seru
m41
–3–
3537
µg/
LRo
om a
ir12
–3.
2–24
5 µg
/m3
Pers
onal
ai
r8
–23
.4–4
95 µ
g/m
3
Turk
ey, 1
982
2,4-
D
herb
icid
e pr
oduc
tion
and
appl
icat
ion
Uri
ne15
Man
ufac
turi
ng:
15 w
orke
rs m
anuf
actu
ring
2,4
-D
este
rs a
nd a
min
e sa
lt; 6
h w
ork
shift
s, ur
ine
colle
cted
on
Frid
ay;
13 2
,4-D
app
licat
or c
rew
men
(p
ilot,
flagm
an, m
ixer
, sup
ervi
sor)
w
ith u
rine
sam
ples
col
lect
ed a
t en
d of
3-m
onth
app
licat
ion
peri
od
Vur
al &
Bur
gaz
(198
4)13
66 µ
g/L
60–9
510
µg/L
13A
pplic
atio
n:71
5 µg
/LN
D–1
920
µg/L
Fore
stry
wor
kers
USA
, 200
2Fo
rest
ry
back
pack
ap
plic
ator
s
Uri
ne5
Gro
up A
: 76
8 ±
438
µg/d
ay;
11 ±
5.7
µg/
kg b
w
per d
ay
Mea
n es
timat
ed to
tal a
bsor
bed
dose
s est
imat
ed fo
r 5 a
pplic
ator
s in
gro
up A
(with
out p
rote
ctiv
e cl
othi
ng),
3 ap
plic
ator
s in
grou
p B
(with
stan
dard
pro
tect
ive
clot
hing
), 1
mix
er/lo
ader
, 1
supe
rvis
or; b
ased
on
daily
24
h ur
ine
sam
ples
col
lect
ed fo
r 6 d
ays
Zhan
g et
al.
(201
1)
3G
roup
B:
951
± 10
89 µ
g/da
y;
13 ±
14.
1 µg
/kg
bw
per d
ay1
Mix
er/lo
ader
: 21
7 kg
per
da
y ±
103
µg/k
g pe
r da
y; 2
.7 ±
1.3
µg/
kg
bw p
er d
ay1
Supe
rvis
or:
257
± 11
7 µg
/day
; 3.
6 ±
1.7
µg/k
g pe
r da
y
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2,4-Dichlorophenoxyacetic acid
9
Cou
ntry
, ye
arJo
b/pr
oces
sM
edia
No.
of
expo
sed
indi
vidu
als
Res
ults
Com
men
ts/a
ddit
iona
l dat
aR
efer
ence
Mea
nR
ange
USA
, yea
r N
RFo
rest
ry
appl
icat
ors
Uri
ne7
Back
pack
:Fi
rst v
oid
urin
e co
llect
ed a
t end
of
peak
app
licat
ion
seas
onG
arry
et a
l. (2
001)
454
μg/L
28–1
700
μg/L
4Bo
om sp
ray:
252
µg/L
86–4
90 μ
g/L
8A
eria
l:42
.9 µ
g/L
ND
–97
µg/L
5Sk
idde
r:17
.6 µ
g/L
0.85
–58
μg/L
15C
ontr
ols:
0.5
µg/L
ND
–1.8
µg/
LU
SA, 1
982
Fore
stry
gr
ound
w
orke
rs
Uri
ne, 2
,4-
D e
xcre
ted
20Ba
ckpa
ck sp
raye
rs:
mea
n, 8
7.6
(N) a
nd
98 (S
) µg/
kg p
er d
ay
24 h
uri
ne sa
mpl
es c
olle
cted
; to
tal a
mou
nt e
xcre
ted
from
the
appl
icat
ion
day
and
4 fo
llow
ing
days
repo
rted
her
e fo
r nor
mal
(N
) and
spec
ial (
S) p
reca
utio
n co
nditi
ons
Lavy
et a
l. (1
987)
20In
ject
ion
bar
wor
kers
: mea
n, 9
.5
(N) a
nd 4
.3 (S
) µg/
kg p
er d
ay20
Hyp
ohat
chet
w
orke
rs: m
ean,
84.
8 (N
) and
39.
5 (S
) µg/
kg p
er d
ay20
Hac
k/sq
uirt
w
orke
rs: m
ean,
28.
8 (N
) and
12.
2 (S
) µg/
kg p
er d
ay
tabl
e 1.
2 (
cont
inue
d)
-
IARC MonogRAphs – 113
10
Cou
ntry
, ye
arJo
b/pr
oces
sM
edia
No.
of
expo
sed
indi
vidu
als
Res
ults
Com
men
ts/a
ddit
iona
l dat
aR
efer
ence
Mea
nR
ange
USA
, NR
Aer
ial
crew
, for
est
appl
icat
ions
Uri
ne, 2
,4-
D e
xcre
ted
3Pi
lots
: mea
n, 1
9.8
(N) a
nd 8
.5 (S
) µg/
kg p
er d
ay
24 h
uri
ne sa
mpl
es c
olle
cted
; to
tal a
mou
nt e
xcre
ted
from
the
appl
icat
ion
day
and
the
follo
win
g 5
days
, rep
orte
d he
re fo
r nor
mal
(N
) and
spec
ial (
S) p
reca
utio
n co
nditi
ons
Lavy
et a
l. (1
982)
3M
echa
nics
: mea
n,
5.45
(N) a
nd 3
.01
(S) µ
g/kg
per
day
3M
ixer
/load
ers:
mea
n, 1
9.6
(N) a
nd
14.0
(S) µ
g/kg
per
da
y3
Supe
rvis
ors:
mea
n,
2.31
(N) a
nd 0
.13
(S) µ
g/kg
per
day
6O
bser
vers
: mea
n,
0.49
(N) a
nd 0
.09
(S) µ
g/kg
per
day
Farm
wor
kers
USA
, 20
00–0
2Fa
rm
appl
icat
ors
Uri
ne
(GM
)68
25 µ
g/L
1.6–
970
µg/L
68 b
road
cast
and
han
d-sp
ray
appl
icat
ors w
ith 2
4 h
post
-ap
plic
atio
n ur
ine;
han
d-lo
adin
g,
body
-load
ing
estim
ates
; air
m
easu
rem
ents
; est
imat
ed to
tal
abso
rbed
dos
es fo
r 14
appl
icat
ors
usin
g ap
plic
atio
n da
y an
d aft
er 4
da
ys o
f 24
h ur
ine
colle
ctio
n
Thom
as e
t al.
(201
0a)
Han
d-lo
adin
g68
0.39
mg
ND
–22
mg
Body
-lo
adin
g68
2.9
mg
0.02
–880
mg
Pers
onal
ai
r68
0.37
µg/
m3
ND
–10
µg/m
3
USA
, 199
6C
usto
m
agri
cultu
ral
appl
icat
ors
Uri
ne
(GM
)15
58 n
mol
/L
[12.
8 µg
/L]
ND
–260
0 nm
ol/L
[N
D–5
75 µ
g/L
5–7
24 h
uri
ne sa
mpl
es d
urin
g 6-
wk
peri
od; e
stim
ated
am
ount
ex
cret
ed in
24
h; a
ir, h
and-
wip
e an
d bo
dy-p
atch
sam
ples
for 2
,4-D
2-
ethy
lhex
yl e
ster
Hin
es e
t al.
(200
1,
2003
)H
and-
load
ing
15–
1.3–
4300
µg/
sam
ple
Body
pa
tche
s15
–0.
3–62
00 µ
g/sa
mpl
e
Pers
onal
ai
r15
–0.
06–2
.4 µ
g/m
3
tabl
e 1.
2 (
cont
inue
d)
-
2,4-Dichlorophenoxyacetic acid
11
Cou
ntry
, ye
arJo
b/pr
oces
sM
edia
No.
of
expo
sed
indi
vidu
als
Res
ults
Com
men
ts/a
ddit
iona
l dat
aR
efer
ence
Mea
nR
ange
Can
ada,
19
81–8
2Fa
rm
appl
icat
ors
Uri
ne, 2
,4-
D e
xcre
ted
6–
215–
6258
µg
6 gr
ound
-rig
spra
y ap
plic
ator
s (o
ne sa
mpl
ed th
ree
times
); 24
h
urin
e sa
mpl
es c
olle
cted
4–7
day
s du
ring
/afte
r app
licat
ion;
tota
l ex
cret
ed 2
,4-D
cal
cula
ted;
han
d-w
ash
and
derm
al-p
atch
sam
ples
fo
r est
imat
ed d
erm
al e
xpos
ures
Gro
ver e
t al.
(198
6)
Han
d-lo
adin
g6
–10
–884
0 µg
Body
-lo
adin
g6
–1.
9–16
99 m
g
USA
, 200
0–1
Farm
ap
plic
ator
sU
rine
(G
M)
3471
.9 µ
g/L
1.5–
2236
Boom
-spr
ay a
pplic
ator
s; m
axim
um 2
4 h
urin
e co
ncen
trat
ions
dur
ing
4-da
y ap
plic
atio
n an
d po
st-a
pplic
atio
n pe
riod
Ale
xand
er e
t al.
(200
7)
USA
, 200
1Fa
rm
appl
icat
ors
and
non-
farm
ers
Uri
ne
(GM
)8
Farm
ers s
pray
ing:
2,
4-D
: 13
µg/L
–U
rine
sam
ples
col
lect
ed 1
–5 d
ays
after
app
licat
ion
and
agai
n 4
wk
late
r
Cur
win
et a
l. (2
005a
)14
Farm
ers n
ot
spra
ying
2,4
-D:
0.48
µg/
L
–
23N
on-f
arm
ers:
0.29
µg/
L–
Can
ada,
199
6Fa
rm
appl
icat
ors
Uri
ne43
Firs
t 24
h sa
mpl
e:12
6 sp
ray
appl
icat
ors u
sing
2,4
-D
or M
CP
for fi
rst t
ime
duri
ng
grow
ing
seas
on; t
wo
24 h
uri
ne
sam
ples
col
lect
ed fr
om st
art o
f ap
plic
atio
n; re
sults
repo
rted
her
e fo
r 43
farm
ers u
sing
2,4
-D
Arb
uckl
e et
al.
(200
2, 2
005)
GM
, 5.
36 µ
g/L;
med
ian,
6.
0 µg
/L; m
ean,
27
.6 ±
72.
5 µg
/L
ND
–410
µg/
L
43Se
cond
24
h sa
mpl
e:G
M,
9.9
µg/L
; med
ian,
12
.0 µ
g/L;
mea
n,
40.8
± 9
1.1
µg/L
ND
–514
µg/
L
Swed
en, N
RTr
acto
r spr
ay
appl
icat
ors
Uri
ne4
8000
µg/
L30
00–1
4 00
0 µg
/LU
rine
sam
ples
dur
ing
wor
king
w
eek
and
after
exp
osur
es, p
erso
nal
air s
ampl
es
Kol
mod
in-H
edm
an
& E
rne
(198
0)24
h e
xcre
tion:
9 m
g–
Air,
pe
rson
al4
–10
0–20
0 µg
/m3
tabl
e 1.
2 (
cont
inue
d)
-
IARC MonogRAphs – 113
12
Cou
ntry
, ye
arJo
b/pr
oces
sM
edia
No.
of
expo
sed
indi
vidu
als
Res
ults
Com
men
ts/a
ddit
iona
l dat
aR
efer
ence
Mea
nR
ange
USA
, 200
3–4
Law
n tu
rf
appl
icat
ors
Uri
ne13
5M
ass e
xcre
ted
duri
ng 2
4 h:
m
edia
n, 1
4.6
µg
0.1–
3658
µg
Spra
yers
sam
pled
acr
oss t
wo
herb
icid
e an
d on
e in
sect
icid
e sp
ray
seas
ons;
two
cons
ecut
ive
24 h
ur
ine
sam
ples
col
lect
ed d
urin
g he
rbic
ide
spra
ying
; not
all
spra
yers
us
ed 2
,4-D
Har
ris e
t al.
(201
0)
Cre
atin
ine-
adju
sted
co
ncen
trat
ions
for
sam
ples
> L
OD
: m
edia
n, 1
0.2
µg/g
0.2–
3001
µg/
g
USA
, 19
94–9
5C
ount
y no
xiou
s wee
d offi
cers
Uri
ne31
Mea
n,
259
± 43
2 µg
/L;
med
ian,
94.
1 µg
/L
0.07
–285
8 µg
/LSe
ason
al c
ount
y ag
ricu
ltura
l no
xiou
s-w
eed
cont
rol a
pplic
ator
s; ov
erni
ght (
appr
ox. 1
2 h)
uri
ne
sam
ples
col
lect
ed e
very
oth
er w
eek
duri
ng se
ason
Bhat
ti et
al.
(201
0)
USA
, 198
0Pa
stur
e sp
ray
appl
icat
ion
Uri
ne2
Cre
w A
dri
ver
and
spra
yer:
1000
an
d 13
00 µ
g/L
resp
ectiv
ely
at 2
4 h
2 dr
iver
s and
2 sp
raye
rs u
sing
tr
uck-
mou
nted
spra
y sy
stem
fo
r pas
ture
land
; mor
ning
voi
d ur
ine
colle
cted
for 3
day
s afte
r ap
plic
atio
n; a
ir sa
mpl
es c
olle
cted
in
truc
k ca
b; h
and
rins
e; c
rew
A
had
sing
le a
pplic
atio
n, c
rew
B h
ad
mul
tiple
app
licat
ions
Dra
per &
Str
eet
(198
2)
Uri
ne2
Cre
w B
dri
ver
and
spra
yer:
4100
an
d 28
00 µ
g/L
resp
ectiv
ely
at 2
4 h
Han
d lo
adin
g–
–1.
2–18
mg
Truc
k ca
b ai
r–
–1.
2–2.
2 µg
/m3
tabl
e 1.
2 (
cont
inue
d)
-
2,4-Dichlorophenoxyacetic acid
13
Cou
ntry
, ye
arJo
b/pr
oces
sM
edia
No.
of
expo
sed
indi
vidu
als
Res
ults
Com
men
ts/a
ddit
iona
l dat
aR
efer
ence
Mea
nR
ange
Can
ada,
19
79–8
0R
ight
-of-w
ay
appl
icat
ors
Uri
ne12
Road
side
gun
spra
yers
: 1.
42 ±
1.7
6 m
g/kg
0.04
–8.1
5 m
g/kg
Elec
tric
righ
t-of
-way
veh
icle
or
back
pack
han
d-sp
ray
appl
icat
ors;
urin
e co
llect
ed in
mor
ning
and
aft
erno
on, t
hen
com
bine
d w
eekl
y on
Thur
sday
s and
dai
ly d
urin
g ai
r-sa
mpl
ing
wee
k
Libi
ch e
t al.
(198
4)
Uri
ne7
Spra
yers
in
Kap
uska
sing
: 6.
16 ±
7.69
mg/
kg
0.27
–32.
74 m
g/kg
Uri
ne3
Mis
t-blo
wer
sp
raye
rs:
2.55
mg/
kg
0.44
–5.0
7 m
g/kg
Air
12Ro
adsid
e gu
n sp
raye
rs:
7.1 ±
4.9
µg/
m3
1.0–
19.5
µg/
m3
Air
3M
ist-b
low
er
spra
yers
: 55
.2 ±
30.
7 µg
/m3
16.2
–91.
3 µg
/m3
Uni
ted
Kin
gdom
, 19
83
Mix
ing/
load
ing
Der
mal
ex
posu
re3
Trac
tor-
mou
nted
: 10
2, 2
44, 1
22 m
g3
trac
tor-
mou
nted
and
2 k
naps
ack
spra
yers
with
six
repl
icat
es e
ach;
w
hole
-bod
y de
rmal
dos
imet
ry
Abb
ott e
t al.
(198
7)
2K
naps
ack:
13.
2,
11 m
gSp
rayi
ngD
erm
al
expo
sure
3Tr
acto
r mou
nted
: 33
.7, 3
8.9,
90.
2 m
g2
Kna
psac
k: 1
59,
89 m
g
tabl
e 1.
2 (
cont
inue
d)
-
IARC MonogRAphs – 113
14
Cou
ntry
, ye
arJo
b/pr
oces
sM
edia
No.
of
expo
sed
indi
vidu
als
Res
ults
Com
men
ts/a
ddit
iona
l dat
aR
efer
ence
Mea
nR
ange
Mal
aysi
a, N
RPa
ddy
spra
y ap
plic
ator
sPe
rson
al
air
NR
Man
ual s
pray
ers:
0.02
7 ±
0.01
9 µg
/LPa
ddy
spra
y ap
plic
ator
s usi
ng
man
ual o
r mot
oriz
ed k
naps
ack
spra
yers
; der
mal
exp
osur
es
estim
ated
from
DR
EAM
mod
el
Baha
rudd
in e
t al.
(201
1)M
otor
ized
spra
yers
: 0.
038
± 0.
0028
µg/
LD
erm
al
expo
sure
NR
Man
ual s
pray
w
ith p
rope
r PPE
: 37
.8 ±
22.
9 pp
mM
anua
l spr
ay
with
out
prop
er P
PE:
86.1
± 5
3.4
ppm
Mot
oriz
ed sp
ray
with
pro
per P
PE:
21.8
± 9
.3 p
pmM
otor
ized
sp
ray
with
out
prop
er P
PE:
45.7
± 2
0.3
ppm
USA
, 201
0Fa
rmw
orke
rsU
rine
361
38.2
% w
ith 2
,4-D
le
vels
> LO
D (L
OD
=
210
µg/L
) 16
% w
ith le
vels
> LL
OQ
(LLO
Q
= 50
µg/
L)
For 6
0 pe
ople
with
sa
mpl
es >
LLO
Q:
GM
, 1.2
8 (r
ange
, 0.
52–1
8.6)
µg/
L
Farm
wor
kers
exp
osed
to m
ultip
le
chem
ical
sRa
ymer
et a
l. (2
014)
Thai
land
, 20
06Fa
rmer
sU
rine
136
2,4-
D d
etec
tion
for 3
7.5%
[75t
h pe
rcen
tile,
0.
66 µ
g/L
(ran
ge,
ND
–598
µg/
L)]
Farm
ers i
n tw
o co
mm
uniti
es;
21 re
port
ed u
se o
f a 2
,4-D
pr
oduc
t but
uri
ne c
olle
ctio
n w
as n
ot sp
ecifi
cally
tim
ed to
an
appl
icat
ion;
mix
ed-c
rop
farm
ers
had
high
er d
etec
tion
rate
s for
2,
4-D
Panu
wet
et a
l. (2
008)
2,4-
D, 2
,4-d
ichl
orop
heno
xyac
etic
aci
d; D
REA
M, d
erm
al e
xpos
ure
asse
ssm
ent m
etho
d; G
M, g
eom
etri
c m
ean;
LLO
Q, l
ower
lim
it of
qua
lifica
tion;
LO
D, l
imit
of d
etec
tion;
MC
P,
4-ch
loro
-2-m
ethy
lphe
noxy
acet
ic a
cid;
NC
, not
cal
cula
ted;
ND
, not
det
ecte
d; N
R, d
ata
not r
epor
ted;
PPE
, pro
tect
ive
pers
onal
equ
ipm
ent
tabl
e 1.
2 (
cont
inue
d)
-
2,4-Dichlorophenoxyacetic acid
15
2010a). Urine samples from farmers in Thailand who were not specifically linked to crop appli-cation had a 75th percentile concentration of 0.66 µg/L (median levels were
-
IARC MonogRAphs – 113
16
tabl
e 1.
3 pa
ra-o
ccup
atio
nal e
xpos
ure
to 2
,4-D
Cou
ntry
/yea
rN
umbe
r of s
ampl
es/s
etti
ngM
edia
Res
ults
Com
men
ts/a
ddit
iona
l dat
aR
efer
ence
Can
ada,
199
692
chi
ldre
n (a
ged
3–18
yrs
) of
farm
2,4
-D o
r MC
PA sp
ray
appl
icat
ors
Uri
neFi
rst 2
4 h
sam
ple:
mea
n, 0
.9 ±
1.4
(max
., 12
) µg
/L
Seco
nd 2
4 h
sam
ple:
mea
n, 1
.9 ±
10.
4 (m
ax.,
100)
µg/
L
9.8–
14.1%
of s
ampl
es >
LO
D;
data
not
repo
rted
sepa
rate
ly
for t
he c
hild
ren
of th
e 43
2,4
-D
app
licat
ors
Arb
uckl
e et
al.
(200
4)
USA
, 200
460
farm
wor
kers
’ chi
ldre
n (a
ged
1–6
yrs)
Uri
neM
edia
n, 0
.14 µ
g/L
41.7
% o
f sam
ples
> L
OD
; no
info
rmat
ion
abou
t 2,4
-D u
seA
rcur
y et
al.
(200
7)N
icar
agua
, 20
08Ru
ral s
choo
lchi
ldre
n; 2
08
urin
e sa
mpl
es fr
om 7
7 ch
ildre
n un
rela
ted
to 2
,4-D
ap
plic
atio
n; 3
sam
ples
afte
r pa
rent
al a
pplic
atio
n of
2,4
-D
Uri
neU
nrel
ated
to a
pplic
atio
n: G
M, 0
.5 (m
ax.,
7.4)
µg/L
Re
late
d to
app
licat
ion:
GM
, 0.4
(max
., 0.
5)
µg/L
Stud
y al
so in
clud
ed d
ata
for
pare
ntal
hou
rs a
nd k
g a.
i. of
2,
4-D
use
d fo
r five
per
iods
fr
om p
re-c
once
ptio
n un
til
8–10
yrs
Rodr
ígue
z et
al.
(201
2)
USA
, 200
0–1
34 sp
ouse
s and
53
child
ren
(age
d 4–
17 y
rs) o
f far
m
appl
icat
ors o
f 2,4
-D sp
ray
Uri
neC
hild
ren:
GM
, 4.9
µg/
L; ra
nge,
ND
–640
µg/
LM
axim
um 2
4 h
urin
e co
ncen
trat
ions
dur
ing
4-da
y ap
plic
atio
n an
d po
st-
appl
icat
ion
peri
od
Ale
xand
er e
t al.
(200
7)Sp
ouse
: GM
, 1.7
µg/
L; ra
nge,
0.5
–24.
9 µg
/L
Can
ada,
199
612
5 sp
ouse
s of f
arm
ap
plic
ator
s of 2
,4-D
or
MC
PA sp
ray
Uri
neFi
rst 2
4 h:
GM
, 0.6
; med
ian,
< 1
µg/
L; m
ax.,
61 µ
g/L;
mea
n, 1
.32
± 5.
6 µg
/L
Seco
nd 2
4 h:
GM
, 0.6
6; m
edia
n, <
LO
D (m
ax.,
100)
µg/
L; a
nd m
ean,
2.0
± 9
.7 µ
g/L
7.0–1
4% o
f sam
ples
> L
OD
; da
ta n
ot re
port
ed se
para
tely
fo
r the
spou
ses o
f the
43
2,4-
D a
pplic
ator
s
Arb
uckl
e &
Ritt
er
(200
5)
Pola
nd, N
R13
spou
ses o
f far
m
appl
icat
ors o
f 2,4
-D sp
ray
Uri
neD
ay a
fter a
pplic
atio
n: m
ean,
3.8
(95%
CI,
0.6–
8.5)
µg/
LJu
rew
icz
et a
l. (2
012)
USA
, 20
02–0
330
farm
ers,
10 n
on-f
arm
ers;
long
itudi
nal c
olle
ctio
n of
ur
ine
sam
ples
dur
ing
1 yr
Uri
neFa
rmer
pre
-pla
ntin
g/off
-sea
son,
pla
ntin
g,
grow
ing/
post
-har
vest
per
iods
: mea
n, 2
.9, 2
2.9,
an
d 7.
8 µg
/g c
reat
inin
e, re
spec
tivel
y
Bakk
e et
al.
(200
9)
Non
-far
mer
pre
-pla
ntin
g/off
-sea
son,
pla
ntin
g,
grow
ing/
post
-har
vest
: mea
n, 0
.5, 1
.35,
and
0.
37 µ
g/g
crea
tinin
e, re
spec
tivel
yU
SA, 2
001
Hou
se d
ust c
olle
cted
from
2
farm
hom
es sp
raye
d w
ith
2,4-
D in
pre
cedi
ng 3
0 da
ys; 3
fa
rms w
ith n
o 2,
4-D
spra
yed;
6
non-
farm
hom
es
Hou
se d
ust
(adj
uste
d G
M)
2,4-
D d
etec
ted
in 1
00%
of t
he fa
rm a
nd n
on-
farm
hom
e sa
mpl
es:
Dus
t col
lect
ed fr
om m
ultip
le
loca
tions
in in
teri
ors o
f ho
mes
dur
ing
each
of t
wo
visit
s
Cur
win
et a
l. (2
005b
)Fa
rms s
pray
ed w
ith 2
,4-D
: 730
ng/
gN
o 2,
4-D
spra
yed:
850
ng/
gN
on-f
arm
hom
es: 3
20 n
g/g
a.i.,
act
ive
ingr
edie
nt; 2
,4-D
, 2,4
-dic
hlor
ophe
noxy
acet
ic a
cid;
GM
, geo
met
ric
mea
n; L
OD
, lim
it of
det
ectio
n; m
ax.,
max
imum
; ND
, not
det
ecte
d; N
R, d
ata
not r
epor
ted;
yr,
year
-
2,4-Dichlorophenoxyacetic acid
17
(a) Water
2,4-D may occur in water as a result of direct aquatic uses; from agricultural, forestry, right-of-way, or turf land applications; through applica-tion-spray drift; or from atmospheric deposition. Concentrations of 2,4-D in water have been measured for drinking-water supplies, surface water, ground water, and for specific application catchment areas (Table 1.4). In a study of drink-ing-water supplies in Mexico, 2,4-D concen-trations for samples above the detection limit ranged from 0.005 to 0.0038 µg/L (Félix-Cañedo et al., 2013). Detection rates for 2,4-D in surface waters varied widely, with overall concentrations ranging from ND to 14.4 µg/L, and central meas-ures typically
-
IARC MonogRAphs – 113
18
tabl
e 1.
4 co
ncen
trat
ion
of 2
,4-D
in w
ater
Cou
ntry
/yea
r of
sam
plin
gN
umbe
r of s
ampl
es/s
etti
ngR
esul
tsC
omm
ents
Ref
eren
ce
Euro
peG
reec
e, 1
988–
2000
2,4-
D m
easu
rem
ent d
ata
com
pile
d fr
om li
tera
ture
for 8
ri
vers
Rang
e of
min
imum
con
cent
ratio
ns, N
D–
0.04
0 µg
/L; r
ange
of m
axim
um c
once
ntra
tions
, 0.
012–
1.2
µg/L
2,4-
D w
as d
etec
ted
at le
ast
once
in 7
out
of 8
rive
rsK
onst
antin
ou e
t al.
(200
6)
Irel
and,
201
242
gro
und-
wat
er sa
mpl
es
colle
cted
from
7 lo
catio
ns2,
4-D
: mea
n, 0
.001
(ran
ge, 0
.002
–0.0
07) µ
g/L
DC
P: m
ean,
0.0
01 (r
ange
, 0.0
01–0
.004
) µg/
L PA
C: m
ean,
0.4
56 (r
ange
, 0.0
15–4
.15a
) µg/
L
PAC
is a
tran
sfor
mat
ion
prod
uct o
r im
puri
ty o
f 2,4
-D
and
MC
PA
DC
P is
a tr
ansf
orm
atio
n pr
oduc
t of 2
,4-D
McM
anus
et a
l. (2
014)
Spai
n, 2
011
7 su
rfac
e-w
ater
sam
ples
from
Eb
ro ri
ver a
nd tr
ibut
arie
s; 32
gr
ound
-wat
er sa
mpl
es fr
om 3
ar
eas o
f the
La
Rio
ja v
iney
ard
regi
on
Rio
ja A
lta: s
urfa
ce w
ater
, mea
n, 0
.045
(ran
ge,
0.02
3–0.
068)
µg/
L; g
roun
d w
ater
, mea
n, 0
.128
(r
ange
, 0.0
46–0
.177
) µg/
L R
ioja
Baj
a: su
rfac
e w
ater
, mea
n, 0
.022
(ran
ge,
0.02
0–0.
024)
µg/
L; g
roun
d w
ater
, mea
n, 0
.031
(r
ange
, 0.0
26–0
.034
) µg/
L R
ioja
Ala
vesa
: gro
und
wat
er, m
ean,
0.0
48
(ran
ge, 0
.034
–0.0
67) µ
g/L
2,4-
D w
as d
etec
ted
in 3
3% o
f th
e w
ater
sam
ples
Her
rero
-Her
nánd
ez e
t al
. (20
13)
Euro
pe12
2 su
rfac
e w
ater
sam
ples
from
>
100
Euro
pean
rive
rs in
27
coun
trie
s
Det
ectio
n in
52%
of s
ampl
es; m
edia
n, 0
.003
µg
/L; m
ean,
0.0
22 µ
g/L;
max
., 1.
221
µg/L
Loos
et a
l. (2
009)
Euro
pe, 2
008
164
grou
nd w
ater
sam
ples
from
23
Eur
opea
n C
ount
ries
Det
ectio
n in
3.7
% o
f sam
ples
; max
., 0.
012
µg/L
Loos
et a
l. (2
010a
)
Euro
pe, 2
007
73 D
anub
e R
iver
and
23
trib
utar
y ri
ver s
urfa
ce w
ater
sa
mpl
es a
cros
s 10
coun
trie
s
Det
ectio
n in
94%
of D
anub
e R
iver
sam
ples
; m
edia
n, 0
.01
(max
., 0.
055)
µg/
L D
etec
tion
in 7
2% o
f tri
buta
ry ri
vers
; med
ian,
0.
003
(max
., 0.
188)
µg/
L
Loos
et a
l. (2
010b
)
Cen
tral
Am
eric
aM
exic
o, 2
008–
9D
rink
ing-
wat
er sa
mpl
es fr
om
7 w
ells
, 4 d
ams,
and
15 m
ixin
g ta
nks f
or su
rfac
e an
d gr
ound
-w
ater
sour
ces s
uppl
ying
60%
of
Mex
ico
City
wat
er
In m
ixed
wat
er: r
ange
, 0.0
05–0
.038
µg/
L2,
4-D
was
foun
d in
20%
of t
he
mix
ed w
ater
; 2,4
-D w
as n
ot
dete
cted
in w
ell a
nd g
roun
d-w
ater
sam
ples
Félix
-Cañ
edo
et a
l. (2
013)
-
2,4-Dichlorophenoxyacetic acid
19
Cou
ntry
/yea
r of
sam
plin
gN
umbe
r of s
ampl
es/s
etti
ngR
esul
tsC
omm
ents
Ref
eren
ce
Nor
th A
mer
ica
Can
ada,
200
3–5
Surf
ace
wat
er c
olle
cted
from
2
refe
renc
e, 5
agr
icul
tura
l, 2
urba
n, a
nd 5
mix
ed a
gric
ultu
ral/
urba
n sit
es
Agr
icul
tura
l site
s: ra
nge
of m
eans
, 0–0
.044
(o
vera
ll ra
nge,
0–0
.345
) µg/
L U
rban
site
s: ra
nge
of m
eans
, 0.0
05–0
.020
(o
vera
ll ra
nge,
0.0
02–0
.063
) µg/
L M
ixed
agr
icul
tura
l/urb
an si
tes:
rang
e of
mea
ns,
0.00
8–0.
357
(ove
rall
rang
e, 0
.002
–1.2
3) µ
g/L
2,4-
D n
ot d
etec
ted
at re
fere
nce
sites
Wou
dneh
et a
l. (2
007)
Can
ada,
200
4M
onth
ly p
reci
pita
tion
sam
ples
co
llect
ed o
ver 5
mon
ths a
t an
agri
cultu
ral s
ite in
the
Yam
aska
R
iver
Bas
in, Q
uebe
c
2,4-
D w
as d
etec
ted
in o
ne (J
une)
out
of
5 m
onth
ly sa
mpl
es, a
t a c
once
ntra
tion
of 0
.007
µg
/L
Aul
agni
er e
t al.
(200
8)
Can
ada,
200
7N
atio
nal s
urve
y of
19
sites
in 1
6 ur
ban
rive
r wat
ersh
eds a
cros
s C
anad
a, in
clud
ing
Paci
fic,
prai
ries
, Ont
ario
, Que
bec,
and
A
tlant
ic g
roup
ings
2,4-
D d
etec
ted
in >
80%
of p
rair
ie a
nd u
rban
ri
ver s
ampl
es; a
cros
s all
urba
n sa
mpl
es; m
ean,
0.
172
µg/L
; max
., >
0.8
µg/L
2,4-
D c
once
ntra
tions
in
crea
sed
from
ups
trea
m
to d
owns
trea
m a
cros
s ur
ban
sites
; hig
hest
2,4
-D
conc
entr
atio
ns w
ere
foun
d in
su
mm
er; 2
,4-D
con
cent
ratio
ns
wer
e sig
nific
antly
2–3
tim
es
high
er a
fter r
ain
Glo
zier
et a
l. (2
012)
USA
, 200
0–1
Surf
ace-
wat
er sa
mpl
es fr
om
Kis
co a
nd M
iddl
e Br
anch
of
Cro
ton
Riv
ers
Kis
co ri
ver:
64%
of s
ampl
es >
LO
D =
0.0
8 µg
/L;
32%
> 0
.1 µ
g/L;
max
., 24
µg/
L M
iddl
e Br
anch
Cro
ton
Riv
er: 5
0% o
f sam
ples
>
LOD
; 13%
> 0
.1 µ
g/L;
max
., 0.
39 µ
g/L
Hig
hest
2,4
-D c
once
ntra
tions
m
easu
red
duri
ng st
orm
flow
co
nditi
ons
Phill
ips &
Bod
e (2
004)
USA
, 199
2–20
0114
65 sa
mpl
es fr
om 6
2 su
rfac
e-w
ater
site
s in
agri
cultu
ral a
reas
, 52
3 sa
mpl
es fr
om 1
9 su
rfac
e-w
ater
site
s in
urba
n ar
eas
Det
ectio
n fr
eque
ncy
of 1
3% in
wat
er fr
om
agri
cultu
ral a
reas
, and
13%
in w
ater
from
urb
an
area
s C
once
ntra
tions
at 9
0th
perc
entil
e: 0
.11 µ
g/L
in
wat
er fr
om a
gric
ultu
ral a
reas
; and
0.16
µg/
L in
w
ater
from
urb
an a
reas
Base
d on
LO
D o
f 0.0
8 µg
/L
in th
e U
SGS
Nat
iona
l Wat
er
Qua
lity
Ass
essm
ent P
rogr
am
USG
S (2
006)
USA
, 200
3–8
Surf
ace
wat
er in
flow
and
out
flow
fr
om a
man
aged
turf
gol
f cou
rse
Inflo
w: m
edia
n, 0
.31
µg/L
O
utflo
w: m
edia
n, 0
.85
(max
., 67
.1) µ
g/L
Out
flow
con
cent
ratio
n w
as
signi
fican
tly h
ighe
r tha
n in
flow
Kin
g &
Bal
ogh
(201
0)
USA
, 200
2–3
Surf
ace-
wat
er sa
mpl
es c
olle
cted
fr
om 7
site
s in
the
uppe
r Pea
rl R
iver
bas
in
Med
ian,
0.1
7 (r
ange
, 0.1
0–14
.4) µ
g/L
Tage
rt e
t al.
(201
4)
a E
xtra
pola
ted
conc
entr
atio
n2,
4-D
, 2,4
-dic
hlor
ophe
noxy
acet
ic a
cid;
DC
P, 2
,4-d
ichl
orop
heno
l; LO
D, l
imit
of d
etec
tion;
max
., m
axim
um; M
CPA
, 4-c
hlor
o-2-
met
hylp
heno
xy a
cetic
aci
d; N
D, n
ot d
etec
ted;
PA
C,
phen
oxya
cetic
aci
d
tabl
e 1.
4 (
cont
inue
d)
-
IARC MonogRAphs – 113
20
tabl
e 1.
5 co
ncen
trat
ions
of 2
,4-D
in re
side
ntia
l dus
t
Cou
ntry
/yea
r of
sam
plin
gN
umbe
r of s
ampl
es/s
etti
ngR
esul
tsC
omm
ents
Ref
eren
ce
USA
, 200
1–7
Hou
se d
ust c
olle
cted
from
27
7 ho
mes
of c
hild
ren
with
le
ukae
mia
, and
306
con
trol
ho
mes
2,4-
D w
as d
etec
ted
in 9
8% o
f hom
es; m
edia
n,
102
ng/g
; 75t
h pe
rcen
tile,
419
ng/
gD
ezie
l et a
l., 2
015
USA
, 200
1–7
Hou
se d
ust c
olle
cted
in 3
33
cont
rol h
omes
in a
cas
e–co
ntro
l st
udy
2,4-
D w
as d
etec
ted
in >
92%
of h
omes
; mea
n,
831
± 60
41 n
g/g
Met
ayer
et a
l. (2
013)
USA
, 199
8–20
00H
ouse
dus
t fro
m 1
12 h
ome
subs
et o
f NH
L ca
se–c
ontr
ol
stud
y
2,4-
D d
etec
ted
in 9
5% o
f hom
es; G
M,
1035
ng/
gTo
tal c
rop
acre
age
with
in
750
m o
f hom
e w
as si
gnifi
cant
ly
asso
ciat
ed w
ith in
crea
sed
2,4-
D
conc
entr
atio
n
War
d et
al.
(200
6)
USA
, 200
0–6
Hou
se d
ust f
rom
66
hom
es in
N
C a
nd 6
2 ho
mes
in O
HO
H: m
edia
n, 1
56 (r
ange
, < L
OD
–21
700)
ng/
g N
C: m
edia
n, 4
7.5
(ran
ge, <
LO
D–7
390)
ng/
gM
orga
n et
al.
(200
8)
USA
, 199
8–20
00H
ouse
dus
t fro
m 5
10 c
ontr
ol
hom
es in
a N
HL
case
–con
trol
st
udy
For c
ontr
ol h
omes
: 110
hom
es <
LO
D; 1
61
hom
es <
500
; 59
hom
es, 5
00–5
99; 1
62 h
omes
, 10
00–9
999;
and
18
hom
es, >
10
000
ng/g
Har
tge
et a
l. (2
005)
USA
, NR
Hou
se in
door
-air
and
surf
ace-
wip
e an
d va
cuum
sam
ples
co
llect
ed a
t 11
occu
pied
and
2
unoc
cupi
ed h
omes
dur
ing
wee
k be
fore
app
licat
ion
and
wee
k aft
er
appl
icat
ion
of 2
,4-D
Mea
n 2,
4-D
con
cent
ratio
ns o
n pa
rtic
les
in a
ir ra
nged
from
app
rox.
1 to
10
ng/m
3 , w
ith d
iffer
ence
s bet
wee
n pa
rtic
le si
ze a
nd
colle
ctio
n pe
riod
; 2,4
-D su
rfac
e lo
adin
gs
rang
ed fr
om 0
.05
to 2
28 µ
g/m
2 for
car
pets
, w
ith lo
wer
val
ues f
or b
are
floor
s, ta
bles
, and
w
indo
w si
lls
Expo
sure
s to
youn
g ch
ildre
n w
ere
estim
ated
to b
e: m
edia
n,
1.37
(max
., 1.
94) µ
g/da
y pr
e-ap
plic
atio
n an
d 2.
42 (m
ax.,
8.87
) µg
/day
pos
t-app
licat
ion;
trac
k-in
fa
ctor
s wer
e im
port
ant
Nis
hiok
a et
al.
(200
1)
2,4-
D, 2
,4-d
ichl
orop
heno
xyac
etic
aci
d; G
M, g
eom
etri
c m
ean;
LO
D, l
imit
of d
etec
tion;
OH
, Ohi
o; N
C, N
orth
Car
olin
a; N
D, n
ot d
etec
ted;
NH
L, n
on-H
odgk
in ly
mph
oma
-
2,4-Dichlorophenoxyacetic acid
21
tabl
e 1.
6 co
ncen
trat
ions
of 2
,4-D
in a
ir
Cou
ntry
/yea
r of
sam
plin
gN
umbe
r of s
ampl
es/s
etti
ngR
esul
tsC
omm
ents
Ref
eren
ce
Can
ada,
200
4W
eekl
y an
d m
onth
ly o
utdo
or
air s
ampl
es o
ver 5
mon
ths
at a
n ag
ricu
ltura
l site
in th
e Ya
mas
ka R
iver
bas
in
Det
ectio
n in
38%
of t
he M
ay–J
une
wee
kly
air
sam
ples
; mea
n, 0
.44
(ran
ge, <
LO
D–1
.31)
ng/
m3
2,4-
D n
ot d
etec
ted
in a
ny o
f the
m
onth
ly a
ir sa
mpl
es c
olle
cted
Ju
ly–S
epte
mbe
r
Aul
agni
er e
t al.
(200
8)
Can
ada,
200
3W
eekl
y ou
tdoo
r air
sam
ples
co
llect
ed a
t 8 si
tes i
n ag
ricu
ltura
l and
rece
ptor
re
gion
s ove
r 1 o
r 3 m
onth
s
At t
hree
pra
irie
site
s, m
eans
rang
ed fr
om 0
.059
to
0.33
1 (o
vera
ll ra
nge,
ND
–1.4
6) n
g/m
3H
ighe
st 2
,4-D
con
cent
ratio
ns
wer
e fo
und
duri
ng ty
pica
l wee
ks
of a
pplic
atio
n
Yao
et a
l. (2
006)
Can
ada,
200
26
wee
kly
outd
oor a
ir sa
mpl
es
at 4
site
s on
a 50
0-km
no
rth–
sout
h tr
anse
ct in
Sa
skat
chew
an
Acr
oss a
ll sit
es: m
ean,
0.3
5 ng
/m3 ,
med
ian,
0.
15 n
g/m
3 ; m
ax.,
2.73
ng/
m3
Hig
hest
2,4
-D c
once
ntra
tions
w
ere
foun
d du
ring
typi
cal w
eeks
of
app
licat
ion
Wai
te e
t al.
(200
5)
Fran
ce, 2
001
4 ou
tdoo
r air
sam
ples
col
lect
ed
at a
n ur
ban
site,
and
5 a
ir
sam
ples
col
lect
ed a
t a ru
ral s
ite
Urb
an si
te: r
ange
, ND
–11
ng/m
3 Ru
ral s
ite: r
ange
, ND
–37
ng/m
3C
once
ntra
tions
in g
as p
lus
part
icle
pha
se re
port
edBa
raud
et a
l. (2
003)
Net
herla
nds,
2000
–118
site
s nat
ionw
ide,
air
and
pr
ecip
itatio
n sa
mpl
es c
olle
cted
on
ce d
urin
g ea
ch 4
-wee
k pe
riod
for 2
yrs
; wee
kly
sam
ples
col
lect
ed a
t thr
ee si
tes
2,4-
D w
as n
ot d
etec
ted
in a
ny a
ir sa
mpl
es
Det
ectio
n in
9%
and
31%
of p
reci
pita
tion
sam
ples
in
2000
and
200
1 re
spec
tivel
y, w
ith m
eans
of 0
.8 a
nd
1.9
ng/L
Dep
ositi
on a
mou
nts t
o so
il an
d su
rfac
e w
ater
s wer
e es
timat
edD
uyze
r & V
onk
(200
3)
USA
, 200
0–1
Hom
e in
door
and
out
door
air
at
66
hom
es in
Nor
th C
arol
ina
and
67 h
omes
in O
hio
Nor
th C
arol
ina,
indo
or a
ir: 7
5th
perc
entil
e,
0.8
ng/m
3 ; m
ax.,
3.7
ng/m
3 O
hio,
indo
or a
ir: 7
5th
perc
entil
e, 0
.8 n
g/m
3 ; m
ax.,
2.0
ng/m
3 N
orth
Car
olin
a, o
utdo
or a
ir: 7
5th
perc
entil
e,
-
IARC MonogRAphs – 113
22
concentrations were observed during weeks when 2,4-D was typically applied. In France, outdoor air concentrations ranged from ND to 11 ng/m3 in an urban location, and ND to 37 ng/m3 in a rural location (Baraud et al., 2003). In a 2-year nationwide monitoring campaign in the Netherlands, 2,4-D was not detected in air, but was detected in precipitation, with mean concentrations of 0.8 and 1.9 ng/L in 2000 and 2001, respectively (Duyzer & Vonk, 2003). In two states in the USA, 75th percentile concen-trations of 2,4-D in indoor residential air were each 0.8 ng/m3, with maximum concentra-tions ranging from 2.0 to 3.7 ng/m3 (Morgan et al., 2008). In the same study, outdoor resi-dential air concentrations of 2,4-D at the 75th percentile ranged from ND to 0.3 ng/m3, with maximum values ranging from 1.7 to 3.2 ng/m3. In other homes with lawn-turf applications, 2,4-D concentrations associated with indoor particulate matter of aerodynamic diameter
-
2,4-Dichlorophenoxyacetic acid
23
application ranged from ND to 7.1 µg/kg bw (Harris et al., 1992).
1.4.4 Exposure assessment to 2,4-D in epidemiological studies
The key epidemiological studies evaluated for 2,4-D in this Monograph can be categorized as occupational studies of applicators in agri-culture settings and farmworkers and one study in the general population. For classification of exposure to 2,4-D, cohort and case–control studies of farmers relied on questionnaire-based approaches to collect information regarding pesticide use, work practices, and other impor-tant agricultural and lifestyle factors such as smoking. Two studies re-analysed several of the case–control studies, applying techniques to consider the use of multiple pesticides by indi-viduals working in agriculture. A study of farm-workers combined extant geographically based data on pesticide application for specific crops, locations, and dates with union-based records
of work history and location information for individuals. The study of the general population examined exposure–outcome relationships using two approaches: (a) questionnaire-based collection of information about residential use of herbicide; and (b) measurement of 2,4-D in house dust as a surrogate indicator of exposure.
There were no epidemiological studies on cancer that relied on measurement of 2,4-D biomarkers for exposure categorization. For 2,4-D, however, the elimination half-life after exposure in humans is short, with ranges of 10–28 hours after an oral dose (Sauerhoff et al., 1977) and 18–68 hours after a dermal dose of 2,4-D, and 18–87 hours for 2,4-D dimethyl amine (Harris & Solomon, 1992). Thus, it is usually impractical to collect adequate numbers of samples to represent long-term exposures in epidemiological cohorts, or to implement collection for large numbers of participants at key time-points such as after herbicide applications. Biomarker measurement therefore has not been the primary means of classifying 2,4-D exposure for research in cancer
table 1.7 concentrations of 2,4-D in food
Country/year of sampling
Number of samples/setting Results Comments Reference
Europe, 2013 2756 food samples analysed for 2,4-D
Only one food (lettuce) had a 2,4-D concentration of > LOQ (the concentration was 0.075 mg/kg)
EFSA (2015)
Europe, NR Residue trial results for 13 plant commodity types
Median and maximum residue values of less than the proposed MRL of 0.05 mg/kg for food commodities, and greater than proposed MRLs ranging from 0.05 to 50 mg/kg for grass, straw, and maize forage commodities
EFSA (2011)
USA, 2000–1 Solid-food duplicate-diet samples collected from children and adult caregivers at 66 homes in North Carolina, and 69 homes in Ohio
North Carolina, child: 75th percentile, 0.9 ng/g; max., 4.4 ng/g Ohio, child: 75th percentile, 0.4 ng/g; max., 20.2 ng/g North Carolina, adult: 75th percentile, 0.9 ng/g; max., 4.0 ng/g Ohio, adult: 75th percentile, 0.6 ng/g; max., 3.7 ng/g
2,4-D detected in
-
IARC MonogRAphs – 113
24
tabl
e 1.
8 ex
posu
re to
2,4
-D in
the
gene
ral p
opul
atio
n
Cou
ntry
/yea
r of
sam
plin
gSu
bjec
ts/s
etti
ngN
o. o
f su
bjec
tsA
ge
(yrs
)M
ediu
mR
esul
tsC
omm
ents
Ref
eren
ce
USA
, 200
9–10
NH
AN
ES g
ener
al
popu
latio
n bi
omon
itori
ng
surv
ey
386
6–11
Uri
ne (μ
g/L)
GM
: 0.3
85; a
nd
95th
per
cent
ile,
1.59
Repr
esen
tativ
e po
pula
tion
sam
ple
for
USA
; dat
a al
so a
vaila
ble
for e
arlie
r tim
e pe
riod
s
CD
C (2
015)
401
12–1
90.
301
and
1.12
1309
20–5
90.
288
and
1.33
651
60–
olde
r0.
349
and
2.08
USA
, 200
0–1
Chi
ldre
n an
d th
eir a
dult
care
give
rs in
Nor
th
Car
olin
a an
d O
hio
66 (N
orth
C
arol
ina)
2–5
Uri
ne (μ
g/L)
Med
ian,
0.5
(r
ange
, < L
OD
–3.
3)
Indo
or a
ir, o
utdo
or a
ir, h
ouse
dus
t, so
il, h
and
wip
e, a
nd fo
od d
ata
also
av
aila
ble
from
this
stud
y
Mor
gan
et a
l. (2
008)
66 (N
orth
C
arol
ina)
Adu
lts0.
7 (<
LO
D–5
.1)
69 (O
hio)
2–5
1.2
(< L
OD
–12.
5)69
(Ohi
o)A
dults
0.7
(< L
OD
–8.1)
USA
, NR
Hom
eow
ner l
awn/
gard
en a
pplic
ator
s and
by
stan
ders
livi
ng in
hom
e
24
(app
licat
ors)
NR
Uri
ne (t
otal
am
ount
2,4
-D
secr
eted
) (μg
/kg
bw)
Rang
e, <
LO
D–7
.1Sa
mpl
es c
olle
cted
for 9
6 h
after
ap
plic
atio
nH
arri
s et a
l. (1
992)
24
(bys
tand
ers)
NR
No
mea
sura
ble
leve
lsPu
erto
Ric
o,
2010
–12
Preg
nant
wom
en15
218
–40
Uri
ne (μ
g/L)
> LO
D in
11.
8%
of sa
mpl
es; 9
5th
perc
entil
e, 0
.6
Max
. val
ue, 0
.9
Spot
uri
ne sa
mpl
es a
t app
rox.
20,
24,
an
d 28
wee
ks o
f ges
tatio
n O
Rs f
or 2
,4-D
det
ectio
n w
ere
signi
fican
tly e
leva
ted
for
cons
umpt
ion
of c
olla
rd g
reen
s and
sp
inac
h in
pre
viou
s 48
h
Lew
is e
t al.
(201
4)
Thai
land
, NR
Chi
ldre
n fr
om
pare
nts w
ith d
iffer
ent
occu
patio
ns:
Uri
ne (μ
g/g
crea
tinin
e)U
rine
firs
t mor
ning
voi
d sa
mpl
es
colle
cted
N
o sig
nific
ant d
iffer
ence
s in
urin
e 2,
4-D
for a
gric
ultu
ral v
s non
-ag
ricu
ltura
l fam
ilies
, or b
oys v
s gir
ls
Panu
wet
et
al.
(200
9)
Farm
er60
12–1
3G
M, 0
.21
(ran
ge,
0.13
–1.0
8)M
erch
ant a
nd tr
ader
3912
–13
0.21
(0.0
9–0.
43)
Gov
ernm
ent a
nd
com
pany
em
ploy
ee52
12–1
30.
17 (0
.10–
0.38
)
Labo
urer
5612
–13
0.19
(0.1
2–1.
87)
2,4-
D, 2
,4-d
ichl
orop
heno
xyac
etic
aci
d; G
M, g
eom
etri
c m
ean;
LO
D, l
imit
of d
etec
tion;
max
., m
axim
um; N
D, n
ot d
etec
ted;
NR
, dat
a no
t rep
orte
d; O
R, o
dds r
atio
; vs,
vers
us; y
r, ye
ar
-
2,4-Dichlorophenoxyacetic acid
25
epidemiology. A recent review summarized rele-vant studies of 2,4-D biomarker measurement, and separately summarized exposure metrics in more recent epidemiological investigations of 2,4-D and cancer (Burns & Swaen, 2012).
This section provides an assessment of the strengths and weaknesses of the exposure assess-ment and assignment methods used in the key epidemiological studies that were evaluated by the Working Group. The detailed discussions of limitations in exposure assessment in the epide-miological investigations described here should not be construed to suggest that these studies are inferior to others in the literature. In fact, in many ways the studies described here have improved on pesticide exposure assessment in this discipline when compared with many studies that relied on less specific exposure-classification categories, such as “farmer” or any non-specific pesticide use.
(a) Studies of occupational exposure
Several studies were based on reported application of 2,4-D in agricultural settings. Exposure assessment in these studies relied on questionnaire-based approaches for reporting use of 2,4-D, together with reporting of factors potentially affecting exposures. Two cohort studies included farm applicators who reported their lifetime use of 2,4-D (Alavanja et al., 2004; Koutros et al., 2013). Three case–control studies included participants who reported using 2,4-D (Brown et al., 1990; Zahm et al., 1990; McDuffie et al., 2001). Three studies performed additional analyses of data from case–control studies to examine joint exposures to multiple pesticides and pesticide classes (Cantor et al., 1992; De Roos et al., 2003; Hohenadel et al., 2011). One study performed additional analyses of data from case–control studies to examine whether reported use of the insect repellent N,N-diethyl-meta-toluamide (DEET) might result in increased penetration of 2,4-D through gloves, and thus increase exposure to 2,4-D (McDuffie et al.,
2005). Another case–control study examined lympho-haematopoietic cancer in farmworkers, with proxy data on pesticide-use locations and amounts combined with work-location history (Mills et al., 2005).
The two cohort-based studies were from the AHS, which collected detailed information on pesticide use and factors potentially affecting exposure (e.g. spraying techniques, personal protective equipment, etc.). Based on the detailed use information, a semi-quantitative expo-sure-assessment method was developed in which estimated intensity was combined with years and annual frequency of use (Dosemeci et al., 2002). The intensity score was based on development of an a-priori exposure-intensity algorithm. Several validity evaluations of the exposure assessment process have been carried out. These included: (i) assessment of the reliability of reporting agri-cultural factors by requiring completion of the enrolment questionnaires twice, approximately 1 year apart; (ii) confirmatory checks corre-lating the years in which a pesticide was report-edly used with dates of registered use of that particular pesticide; and (iii) comparison of the exposure algorithm with external exposure data. Agreement between reporting of ever/never use of specific pesticides and application practices was high, and generally ranged from 70% to > 90%. Agreement was lower (typically 50–60%) for duration or frequency of use of specific pesticides (Blair et al., 2000). The confirmatory checks on reported usage of specific pesticides established that the majority of respondents provided plausible responses for both decade of first use and total duration of use (Hoppin et al. 2002). The exposure-intensity algorithm was evaluated using measurements of 2,4-D urinary biomarkers in the AHS cohort and in two other studies (Coble et al., 2005; Acquavella et al., 2006; Thomas et al., 2010b). When combined, these studies showed that the AHS algorithm had