Residential Proximity to Agricultural Herbicides

During Pregnancy and Childhood Leukemia in

the Danish National Birth Cohort

Deven Patel, PhD, MPH

Occupational and Environmental Epidemiology Branch,
Division of Cancer Epidemiology and Genetics

ISES/ISEE Joint Conference

August 29th, 2018
Pesticides and childhood leukemia

 Maternal occupational and home/garden pesticide use during the

pregnancy associated with increased risk of childhood leukemia in
meta-analyses (Wigle, 2009)
 Studies have been primarily case-control
 Few studies could evaluate specific
active ingredients

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Residential exposure to agricultural pesticides

 Proximity of a home to crop fields increases pesticide exposure (reviewed

by Deziel, 2017)

 Increased crop density within 500m-750m of home associated with

increased indoor pesticide concentrations in house dust (Ward et al. 2006;
Gunier et al. 2008)

 Higher urine concentrations of pesticide metabolites in both adults and

children living in agricultural areas (Bradman et al. 2005; Lambert et al. 2005)
 A few ecologic studies found increased risk of childhood cancers
associated with crop density (Booth et al. 2015; Carozza et al. 2008)

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 Agriculture in Denmark

 61% of land cover is agricultural

Major crops:
- Cereals (spring/winter)
- Grass clover
- Rapeseed
- Sugar beets
- Peas
- Maize (feed corn)
- Potatoes
- Other vegetables

Copernicus Land Monitoring Service

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Herbicide use in Denmark
Commonly applied herbicides:
- Glyphosate
- Pendimethalin
- Fluroxypyr
- Bromoxynil/Ioxynil
- Tribenuron-methyl
- Prosulfocarb
- Phenmedipham
- Propyzamide
Eurostat - Thifensulfuron-methyl

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Specific aims

Aim 1
Examine the association between crop area near the home during
pregnancy and childhood leukemia risk

Aim 2
Examine the association between herbicide applications near the
home during pregnancy and childhood leukemia risk

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Study population
Danish National Birth Cohort (DNBC)
 Prospective, national, cohort of ~100,000 women and children (pregnancies
between 1996-2003)
 Childhood cancer cases (aged <15) identified from the Childhood Cancer
Registry through 2015

Current study
 191 Childhood cancer cases [median age: 4 (IQR: 2-7)]
 61 childhood leukemias, 44 ALL (72%) and 17 AML (28%)
 10% random sample of non-cases
 N= 9,362 (excluding children with Down syndrome and non-singleton births)
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Geospatial herbicide exposure assessment
AIM 1: Crop Area
 Geocoded all addresses during pregnancy
- accounting for those who moved (~6%)
 Calculated area (hectares) of 8 major
crops for a range of circular buffer
distances from home (100m-1000m)
 Presenting hectares within 500m of home
AIM 2: Herbicide Application
Pesticide Known
Sales Data Application
(1996-2003) Rates (2012- )
 Agronomist collaborator adjusted
application rates from 2012 by sales data
to get adjusted monthly application rate
 All months of pregnancy excluding months
crops not grown
 Herbicide application (grams) =
adjusted application rates X crop area
 Limited to herbicides used on ≥20% of
hectares of at least one major crop
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Statistical analyses
 Cox proportional hazard regressions to compute HRs and 95% CI
Common reference group: those with no crop area within 500m of their home
Aim 1: Crop area (overall & by crop type)
- comparing those with low and high crop area (≤median, >median)
with reference group
Aim 2: Herbicide applications (by specific active ingredient)
- comparing those with low and high estimated herbicide application
(≤ median, >median) with reference group
 Adjusted for maternal age at pregnancy and gender of child
 Parental occupation data available, but <1% in mothers and <4% in fathers

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Results: Distribution of crop acreage within 500m of homes

Crop Type* Percent of study

population with >0  Total area in 500m: 78 hectares
hectares in 500m
buffer  Median crop area (total): 14 hectares
ALL CROPS 63% (IQR: 4-29)
Winter Cereal 53%
 Moderate correlations (spearman rho:
Spring Cereal 52%
Grass Clover 38%
0.50-0.60) between:
Winter Rapeseed 26% - spring + winter cereals
Other Seed 17% - spring cereals + grass clover
Sugar Beets 17%
Peas 18%
Maize 12%

*Other vegetables, spring rapeseed, and potatoes

had very low acreage and were not included in
analyses

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Childhood leukemia and total crop area within 500m of homes

HR: 1.89 (1.03-3.50)

HR: 1.10 (0.61-2.33)

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Childhood leukemia and crop area within 500m of homes for 8 major
crop types
Crop Type Area (Hectares) Cases Hazard Ratio 95% CI
Reference* 0 17 -- --
Winter Cereals <4.3 19 1.3 0.7, 2.6
4.3-55.6 25 1.7 0.9, 3.2
Spring Cereals <2.5 20 1.4 0.7, 2.7
2.5-46.1 24 1.7 0.9, 3.1
Grass Clover <0.2 13 0.92 0.4, 1.9
0.2-31.6 31 2.2 1.2, 3.9
Winter Rapeseed 0 27 1.6 0.9, 2.9
>0-15.4 17 1.4 0.7, 2.8
Other Seed 0 35 1.7 0.9, 3.0
>0- 24.0 9 1.2 0.5, 2.7
Sugar Beets 0 29 1.4 0.8, 2.5
>0-19.9 15 1.9 0.9, 3.9
Peas 0 27 1.3 0.7, 2.5
>0-11.6 17 2.0 1.0, 4.0
Maize 0 31 1.3 0.7, 2.4
>0-19.5 13 2.4 1.1, 4.8
* Reference group was those with no crop area near the home
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Herbicides with high application rates (g/ha), by crop type

Spring and Winter Cereals

Winter Rapeseed (26%)
(52-53% participants with any area)
 Propyzamide
 Glyphosate
Sugar Beets (17%)
 Pendimethalin (also on peas)
 Phenmedipham
 Bromoxynil/ioxynil/fluroxypyr *
Maize (12%)
 Prosulfocarb  Trifensulfuron-methyl
 Tribenuron-methyl
*highly correlated (>0.90), combined in analyses

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Childhood leukemia and herbicides used on cereals (grams) within
500m of the homes
Herbicide Range (g) Cases Hazard Ratio 95% CI
Reference Group* 0 17 1.0 --

glyphosate 0-3434 24 1.8 0.9-3.4

3435-51,610 21 1.6 0.8-3.0
pendimethalin 0-109 20 1.7 0.9-3.2
110-18,517 24 2.0 1.1-3.6
bromoxynil/ioxynil/fluroxypyr 0-38 21 1.8 0.9-3.5
38-3,828 24 2.1 1.1-3.9
prosulfocarb 0-60 26 2.3 1.2-4.2
61-30,481 19 1.7 0.9-3.2
tribenuron-methyl 0-0.7 20 1.5 0.8-2.9
0.8-202 25 1.9 0.9-3.5
* Reference group was those with no crop area near the home

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Childhood leukemia and herbicides used on other crops (grams)
within 500m of the homes

Herbicide Range Cases Hazard Ratio 95% CI

Reference Group*
0 17 1.0 --
propyzamide 0-0.02 24 1.7 0.9-3.1
(winter rapeseed) 0.03-4,381 20 1.4 0.7-2.7
phenmedipham 0-0.01 21 1.5 0.8-2.8
(sugar beets) 0.02-16,966 23 1.6 0.9-3.0
thifensulfuron-methyl 0-0.07 19 1.4 0.7-2.6
(maize) 0.08-78 25 1.8 0.9-3.2
* Reference group was those with no crop area near the home

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Summary and discussion
We found elevated risk of childhood leukemia with:
 Higher total crop area [>14 hectares of crops], mostly from cereals
 Higher area of spring and winter cereals
 Presence of less common crop types (grass clover, peas, maize)
 Higher application of specific herbicides
- Cereal herbicides: pendimethalin and bromoxynil/ioxynil/fluroxypyr
- Elevated, but not significant, risk for phenmedipham (Sugar Beets) and
thifensulfuron-methyl (Maize)

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Strengths

 Crop density measured at the individual-level

 Estimated specific herbicidal active ingredient use
 Complete residential history during pregnancy
 Prospective study

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Limitations

 Locations of crops where herbicides were applied not known

 Limited sample size
 No information on:
- home/garden use (important for glyphosate and pendimethalin)
- Other agricultural exposures (e.g. farm animals or concentrated feeding
operations)

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Future analyses

 Additional analyses in DNBC cohort:

- Expand study to other pesticide types used on high proportions of
crops
- Analyses of exposures at specific trimesters
 We will follow-up these interesting findings in a national record-linkage
study in Denmark, using detailed pesticide use data (2012-2016)

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Collaborators

 National Cancer Institute  University of Illinois at Chicago

Mary H. Ward Leslie T. Stayner
Rena R. Jones
 Aarhus University (Denmark)
Steen Gyldenkærne
Thomas Becker
 Staten Serum Institute (DNBC)
Sjurdur F. Olsen Email:
Charlotta Granström pateldem@nih.gov

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Supplemental: Proportions of hectares treated with
pesticide active ingredients (2012)

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