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!