1. Institute for Risk Assessment Sciences
Overview of exposure assessment methodological issues for epidemiological studies on pesticides
Hans Kromhout
Institute for Risk Assessment Sciences
Utrecht University

2. Farmers (used to be) Conservative Stable: career and residency
Knowledgeable
Well-informed (by extension workers)
Fond of their work
So what’s the problem when we want to study their agricultural exposure?

3. Nature of exposures in agriculture
Seasonal
Often outdoors
Highly variable
Type of agent and exposure
Biological, chemical and physical
Individual agents (active ingredients)
Intensity, duration and frequency

4. It is a miracle we find any exposure-response relation at all
Given nature of exposures in agriculture and potential for misclassification
It is a miracle we find any exposure-response relation at all

5. How bad is it?
Based on inhalation exposure database (Kromhout et al. Annals Occup Hyg 1993):
Individuals working outdoors in intermittent process have on average:
Day-to-day concentrations vary up to a factor 150
Between-worker averages vary up to a factor 10
Individual working indoors in intermittent process have on average:
Day-to-day concentrations vary up to a factor 90

6. How bad is it?
Based on dermal exposure database (Kromhout & Vermeulen, Annals Occup Hyg 2001):
For re-entry workers exposed to pesticides on average:
Day-to-day concentrations vary up to a factor 10-40
No between-worker differences in average exposure
For sheep dippers:
Day-to-day concentrations vary up to a factor 300
Between-worker averages vary up to a factor 30
Huge differences between body parts!!!

7. Fruit growers exposed to Captan during re-entry Captan in NL 1991 and 1992
Type N K
bwR.95
wwR.95
Inhalation
154
108
3.1
541
Dermal wrist
188
133
17.3
143
Dermal hands
182
128
45.1
65.3

8. Relative contributions of main tasks and routes to exposure to Captan (de Cock et al. 1996)
Farmer
Son
Wife
Growing season
Inhalable exposure
Dermal exposure
Application 4% 1% 0% 6% 2%
Re-entry
95%
98%
91%
84%
87%
47%
Home 9%
10%
11%
53%
Harvesting season
<1% 3%
97%
99%
89%
93% 7% 5%
17%
Total amount 81 88 33
440
468
211

9. Consequences for epidemiological research
Generic questions possible in general population based studies (case-control) resulting in considerable contrast between exposed and non-exposed
Studies within agriculture suffer from lack of contrast and lack of accuracy and precision
Using measurements will not necessarily result in more accurate exposure assessment since:
Mixed exposure situations
Large variability (not enough data available)
Good modelling practices needed

10. Used Methods Self-reports Expert-assessment Job-exposure matrices
Crop-exposure matrices
Algorithms (determinants of exposure)

11. Self-reports versus expert assessment case-control neuroblastoma (Daniels et al. 2001)
Very low prevalence (3.8% fathers, 0.7% mothers)
Fathers an OR of 1.5 ( ) (comprehensive OH review)
Self-reports substantially higher: 7.5% and 3.4%, but 49% of fathers and 80% of mothers were unlikely to have been exposed; showed no relation with outcome
Exposure classification based on job title showed opposite patterns; mothers an OR of 3.2 ( )
Standardized and validated questions
focussing on determinants needed

12. JEMs
For the general population we need exposure assessment to be very specific because of the low prevalence: only individuals with a high probability of exposure should be assigned exposure to pesticides
As long as we make the exposure axis not to specific we will be fine
For agricultural cohorts we will need more detailed job and agent axes Crop Exposure Matrices

13. CEMs Crop exposures rely often on registration data
But multiple pesticides can be used on a specific crop
Also same pesticide can be used on multiple crops
Results in a very sensitive method, but given the high prevalence within agricultural studies this shouldn’t be too problematic
However it will result in (heavily) correlated exposures

14. Agricultural Health Study Algorithm (Dosemeci et al. 2002)
So will semi-quantitative methods as elaborated by Dosemeci work?
Algorithm scores appear to provide a reasonably valid measure of exposure intensity (Coble 2005); but appeared marginally predictive of forearm captan exposure and did not predict air, hand rinse or urinary THPI exposures (Hines 2008); improved algorithm(Coble 2011)
Re-entry exposure component (with most likely a longer duration) has to be included (Negatu 2016)
We cannot change anything about the mixed and highly variable exposure environment of the applicator

15. Conclusions
If you are looking for positive results when studying chronic effects of pesticides exposures, go for the case-control design and study the general population. (You will need large studies)
We will only find meaningful relationships between pesticides exposures and chronic health effects if we know how to deal with the inherent large temporal and spatial variability in these exposures

16. Thank you very much for your attention!