9.4 f.m. rubino
TRANSCRIPT
Nuove sfide per la medicina del Lavoro: Immigrazion e, Promozione della salute
A quantitative approachA quantitative approach
to the determinationto the determination
of provisional of provisional BEIsBEIs for pesticidesfor pesticides ..
International Symposium on Biological MonitoringManchester (UK) September 9-11 2013
Federico Maria Rubino, Stefan Mandic-Rajcevic, Giorg io Vianello, Eugenio Ariano b, Claudio Colosio.Department of Health Sciences, Università degli Studi di Milano, via A. di Rudinì, 8 I-20142 MilanoItalian and International Centre for Rural Health – WHO Collaborating Centre;bLocal Health Unit of Lodi, Piazza Ospitale, 10, I-26900 Lodi, Italia.
CONTENTS
�PESTICIDES & FARMERS’ HEALTH HAZARD
�TOOLS FOR RISK ASSESSMENT
�BIOLOGICAL MONITORING FOR RA
�BASIS FOR BIOLOGICAL EXPOSURE INDEX
�EXAMPLES OF APPLICATION
•Unavoidable use in agriculture & public health
•Unavoidable health hazard
•Necessity of risk assessment
• Industrial hygiene approach NOT applicable
•Among best-known chemicals
•Extensive information exploitable
•Health-based exposure limits AVAILABLE
GENERAL INFORMATION ON PESTICIDES
•Acceptable Daily Intake (ADI)
•Acute Reference Dose (ARfD)
•Acceptable Operator Exposure Limit (AOEL)
EXPOSURE LIMITS FOR PESTICIDES
Safety forGeneral Population
•Systemic doses•milligrams / kg body weight] day
Maximum amount of active substance to which the operator may be exposed from any route of absorption without any adverse health effects.
from
SYSTEMIC DOSEto
MEASURABLE PARAMETER(‘BEI’)
ACGIH’S BEIs ® = “ the levels of determinants that are most likely to be observed in specimens collected from healthy workers who have been exposed to chemicals to the same extent as workers with inhalation exposure at the Threshold Limit Value ”
DEFINITION OF BIOLOGICAL EXPOSURE INDEXFOR PESTICIDES
Provisional BEIs for pesticides can be defined as “ the levels of determinants that are most likely to be observed in specimens collected from healthy workers who have been exposed to pesticides to the same extent as workers with dermal and inhalation exposure at the AOEL value ”
Biomarkerlevel
Worker individual exposure
Protection limit
0,1 1 10 100
�
�
�
�
�
�
�
�
�
�
�
Biomarker level@
Protection limit
Concept for BEI
as AOELequivalents
Exposure-proportionalHealth risk
Exposure-proportionalBiomarker level
Health risk-proportionalBiomarker level
“Safer”
“Risky”EXPOSURE = 1 AOEL
TOOLS FOR RISK ASSESSMENT
• MEASUREMENT• Direct method• washing feasible onlyfor the hands
• Indirect method• pads: estrapolation!• whole body: $$$! ; artifactual
• biological monitoring• In urine: limit valuesUNAVAILABLE
CONJECTURE• pre-marketing modelsPhysically-based reconstruction
from poorly representativevalues of parameters
Some parameters aren’t• transparent (default values)• adaptable to local situations• User-modifiable
DIFFICULT TO APPLYGIGO?
•pesticide dose at skin in relevant exposuretime frame before excretion
•pesticide skin absorption (%)•pesticide Acceptable Operator ExposureLevel (AOEL, in mg/kgbw]day)
Biological Exposure Index (BEI)from:x-axis
•pesticide biomarker excreted in 24-hour urine•individual body mass (kg) of exposed subject
y-axis
Strategy for field monitoring
Field monitoring :• clothing contamination• hand washing
structured Interviews&
information collection
Causes of exposure
Contamination of work clothingAssessment of protection affordedby working conditions
Biologicalmonitoring:•urine collection
Toxicologicalrisk assessment
pre- and post-application urine
Front - clothed Back - clothed Front - unclothed Back - unclothed
Hand-wash liquid
1
2 3
4
56 7
8 9
10
10 x 10 cm
Contamination on clothes Contamination below clothes
Skinexposure
+ all-routeabsorption
Esposure assessment: the pads method
Calculate doseASSESS EXPOSURE-PROPORTIONAL RISK
systemicdose
skindose
* skin absorption(%)
=
Information present in Authorization dossier(if not measured or calculated, default = 100%)
Subject to uncertainty in measurement or estimation
milligram
Calculate individual limitAcceptable Operator
DoseAcceptable Operator
Exposure Limit (AOEL) *body
weight=
milligram = milligramkg body weight
* kg
ASSESS EXPOSURE-PROPORTIONAL BIOMARKER
•24-HOURS PRE-TREATMENT ���� ‘blank ’ sample•24-HOURS AFTER-TREATMENT ���� ‘exposure ’ sample
Laboratory analysis (HPLC-MS-MS)
URINE SAMPLE COLLECTION
•24-HOURS PRE-TREATMENT ���� ‘blank ’ sample•Separate collection of individual mincturictions for 24-HOURS AFTER-TREATMENT ���� ‘exposure ’ sample
or:
Biomarkerlevel
0,1 1 10 1000
�
�
�
�
�
�
�
��
��
Worker protection = Protection limit / exposure
“Safer”Protection limit
Biomarker level@
Protection limit
pRisk
Concept for BEI in pesticide application
BEI���� Biological Exposure Index
1. herbicide PROPANIL in maize
(Tox Lett 2012; 213(1):49-56. PMID: 21903154)
2. fungicide MANCOZEB in vine
3. fungicide TEBUCONAZOLE in vine
(in preparation)
Real-life exposure studies (2008-2013)
•Fungicide• AOEL = 0.035 mg*kg -1]die
•Dermal absorption:�0.11% by 8 hours (high
level dose formulation)�0.24% by 8 hours (low
level dose formulation)
• ARfD = 0.6 mg*kg -1]die
• ADI = 0.05 mg*kg -1]die
NH NH
SMn
S
S S
n
* Znm
NH
NH
S
Ethylene-bis-thiourea
Example - mancozeb
• 14 farmers applied mancozeb on vineyards• 8 applied for 1 day (one twice in different months)• 3 applied for 2 consecutive days• 3 applied for 3 consecutive days
• On-cloth and under-cloth sampling pads (8 per day)• Hand washes (1-3 per day)• Pre- and post-application 24-hour urine
Samples collected
Hill & Flatland vineyard – Lombardy
• 16 farmers applied mancozeb on vineyards• 16 applied for 1 day (one twice in different months)
EXCRETION OF ETHYLENETHIOUREA (MANCOZEB METABOLITE)
0
5
10
15
20
25
30
1 2 3 5 6 7 8 9 10 12 13 14 15 27 28 29
Vineyard farmers taking part in the study
cut-off (95% percentile) of the Italian population(Colosio et al. , 2005)
4,7microgg creat
microgramg creat ■ Pre esp
■ Esp 1°g
Flatland vineyard - Lambrusco
0
1
10
100
1.000
1 10 100 1.000 10.000 100.000 1.000.000
URI-postinfricalcsup
micrograms24h post-exp 110 micrograms
Worker protection= Protection limit / exposure
ETU excretion vs. protection
propanil excretion vs. protection
1 mg/24h
Toxicol Lett 2012; 213(1):49-56. PMID: 21903154
1
10
100
0 1 10 100 1.000 10.000 100.000 1.000.000
Biomarkerlevel
Worker protectionAOEL / exposure
Biomarker level@
Protection limit
= y
= x
intercept
slopeαααα
y = 10^ * x^intercept slope
Log(y) = + * Log(x)intercept slope
BEI = 10^intercept
x = 1
= 1 ∀∀∀∀ slope
from log-logto lin-lin
= 1,5
= - 0,25
BEI = 10^1.5 = 31.6
Concept for BEI in more detail - 1
The same function plotted as linear-linear relationship
0
5
10
15
20
25
30
35
40
45
50
0 250 500 750 1.000MigliaiaWorker protectionAOEL / exposure
Biomarkerlevel
Biomarker level@
Protection limit
= 10^ * ^1.5 - 0.25
Biomarkerlevel
AOELexposure
x = 1
not dependanton
occupationalexposure
dependant onoccupationalexposure
Above this levelof worker protectionbiological monitoring
is ineffectiveto assess effect
of prevention
Concept for BEI in more detail - 2
y vs x scala LIN-LIN
0
5
10
15
20
25
30
35
40
45
50
0 5 10x = PROTECTION = AOEL / syst.dose
Biomarkerin urine
play media inf y
sup y PROTECTION = 1
sec1,2 sec2,3
sec1,3 INTERSECTION
Serie9 INTERSECTION
intersez x dato y
SLOPE = - 0.25INTERCEPT = 1.50
Limit of meaningfulness ofbiological monitoring
Concept for BEI in more detail - 3
¼ to 1/10of AOEL
CONCLUSIONS
�BIOLOGICAL MONITORING IS A FEASIBLE TOOL FOR RISK
ASSESSMENT OF PESTICIDE USE IN AGRICULTURE
�THERE IS A RATIONAL BASIS TO DERIVE BIOLOGICAL EXPO SURE
INDEX FROM REAL-LIFE FIEL MESUREMENTS
�EXAMPLES OF APPLICATION SHOW A RATIONALLY-BASED
DISCRIMINATION BETWEEN INTERVENTION-RELEVANT AND NO -
INTERVENTION AREAS
THANK YOU THANK YOU
FOR ATTENTION!FOR ATTENTION!