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10.4 Rossbach
1. Institute of Occupational, Social-,
and Environmental Medicine
Uptake and elimination of permethrin related to
the use of permethrin treated clothing for
forestry workers
B. Rossbach, A. Niemietz, P. Kegel, S. Letzel
Institute of Occupational-, Social-, and Environmental Medicine
University Medical Center of the Johannes Gutenberg University, Mainz, Germany
The 9th International Symposium on Biological Monitoring in Occupational and Environmental Health
9th – 11th September 2013, Lowry Centre, Manchester, UK
2. Institute of Occupational, Social-,
and Environmental Medicine
Background Information
Clothing with long-lasting permethrin treatment is sold to
improve protection against tick related diseases
Use of respective clothing entails uptake of permethrin into
the body
Uptake by the dermal route likely
Dermal uptake of permethrin slow in general,
typical rate of uptake: 2% of the applied dose[1]
After uptake: metabolic cleavage, conjugation and
excretion of metabolites in urine
Excretion half-lifes after dermal uptake from
permethrin containing ointments: about 30h[2]
[1]
Appel et al., Int. J. Hyg. Environ. Health, 211: 88 (2008); [2] Tomalik-Scharte et al., Eur J Clin Pharmacol, 61: 399 (2005)
2
3. Institute of Occupational, Social-,
and Environmental Medicine
Properties of Permethrin
Neurotoxin in target organisms (insects, mites) after contact or uptake
Effects in humans:
•
Local effects: reversible unpleasant sensations (prickling, numbness, itching),
dermal and mucosal irritations, respiratory tract irritation
•
Systemic effects: headache, dizziness, fatigue, intestinal disorders, nausea, vomiting
•
Inconsistent classification with respect to carcinogenicity (IARC Cat. 3: not classifiable, USEPA: “likely to be carcinogenic to humans after oral uptake”)
No biomonitoring limit value such as BAT or BEI available
Environmental background exposure in the general
population, reference values available for Germany
WHO acceptable daily intake (ADI):
0,05 mg/kg body weight[3]
[3] World
Health Organisation (WHO)/Food and Agriculture Organization (FAO) Pesticide residues in food 1999
Evaluations Part II - Toxicology: Permethrin, 1999
3
4. Institute of Occupational, Social-,
and Environmental Medicine
Main Issues of our Study
What is the internal permethrin exposure of persons,
who wore permethrin treated clothing for just one day?
What are the kinetics of uptake and excretion like?
Is there a favorable time range for monitoring internal
exposure?
Is there an influence of climate and/or physical
workload on internal exposure when wearing
permethrin treated clothes
4
5. Institute of Occupational, Social-,
and Environmental Medicine
Study Design
N= 30 male volunteers (age 20-34 years, median 25)
Wearing of permethrin treated clothing for forestry workers (long
sleeved jacket and long pants), three times for 8h each
Undergarments standardized
Varying external conditions (“wearing conditions”)
I.
Comfort conditions without any further restrictions
regarding the subjects´ whereabouts over the whole 8h period
II.
At the minimum 4h stay under condition of increased
temperature (≤ 25°C and ≤ 65% rel. hum.)
III. Like II., additional simulation of physical workload using
a bicycle ergometer (six 10-min-intervals with HR 140-150 min-1)
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6. Institute of Occupational, Social-,
and Environmental Medicine
Study Design
Collection of 12 urine samples in total; collection before,
during and after wearing permethrin treated clothes
Time of sampling and particular type of sample in detail:
spot urine sample
“wearing period”
0
0
0
8
16
2420
32
20
40
40
40
48
6072
80
96
8h urine sample
0
40
100 120 120 20144
140 504 500
Zeit ab beginning of wearing [h]
time fromTragebeginn [h]120
60
80
100
140
500
60
Zeit ab T
Zeit ab Tragebeginn [h]
Timespan between repeated wearing of clothing under
differing conditions: at least 3 weeks
6
7. Institute of Occupational, Social-,
and Environmental Medicine
Determination of Internal Exposure
Metabolism scheme of permethrin
Analytical method[4]
(simplified)
Urine sample (10 ml)
Cl
O
Cl
O
O
Acidic hydrolysis
cis/trans permethrin (mixture of isomers)
R
Cl
OH
Cl
HO
pH-controlled liquid/liquid
extraction
O
O
trans-DCCA
Derivatization
+
R
Cl
OH
Cl
O
cis-DCCA
[4]
HO
O
O
Analysis by
gas chromatography/
tandem mass spectrometry
(GC/MS-MS)
3-PBA
according to Schettgen et al., J. Chrom. B, 778: 121 (2002)
7
8. Institute of Occupational, Social-,
and Environmental Medicine
Time Curve of DCCA-Excretion
Pooled analysis of “wearing conditions” I to III
DCCA in urine [µg/l]
100
maximum average excretion: 12,1 µg/l
10
maximum
1
mean
minimum
0.1
period of wearing
„reference value“
general population[4]
0.01
0 8
20
40
60
80
100
120
140
500 510
Time [h]
8
[4] German
Federal Environmental Agency, Bundesgesundheitsbl. Gesundheitsforsch. Gesundheitsschutz, 48: 1187 (2005)
9. Institute of Occupational, Social-,
and Environmental Medicine
Time Curve of DCCA-Excretion
DCCA in urine (mean conc.) [µg/l]
Separate analysis of “wearing condition” I to III
wearing condition
I
II
III
10
1
Maximum values (percentage of samples > “reference value“):
condition I:
8.6 µg/l (53%)
condition II:
12.9 µg/l (61%)
condition III:
15.0 µg/l (79%)
period of wearing
„reference value“
general population[4]
0.1
0 8
20
40
60
80
100
120
140
500 510
Time [h]
9
[4] German
Federal Environmental Agency, Bundesgesundheitsbl. Gesundheitsforsch. Gesundheitsschutz, 48: 1187 (2005)
10. Institute of Occupational, Social-,
and Environmental Medicine
Elimination Half-lifes
DCCA in urine (mean conc.) [µg/l]
Calculation by linear regression, regarding samples from 20 to 144 h from
beginning of wearing
wearing condition
I
II
III
10
1
t1/2cond I
: 36,2 h
t1/2cond II
: 30,9 h
t1/2cond III
: 30,0 h
0.1
0 8
20
40
60
80
100
120
140
500 510
Time [h]
10
11. Institute of Occupational, Social-,
and Environmental Medicine
Comparison of Excreted Amounts
Comparison of Area Under the Curves (AUC) resulting for different wearing
conditions
DCCA in urine (mean conc.) [µg/l]
16
wearing condition
I
II
III
14
12
10
𝑐𝐼𝐼𝐼
𝐴𝑈𝐶0−144 = 𝟖𝟑𝟏
µ𝑔 ∙ ℎ
(= 0.96 ∙ 𝐴𝑈𝐶0−∞ )
𝑙
8
+72%
𝑐𝐼𝐼
𝐴𝑈𝐶0−144
𝑐𝐼
𝐴𝑈𝐶0−144
6
4
µ𝑔 ∙ ℎ
= 𝟔𝟑𝟒
(= 0.94 ∙ 𝐴𝑈𝐶0−∞ )
𝑙
µ𝑔 ∙ ℎ
= 𝟒𝟖𝟐
(= 0.91 ∙ 𝐴𝑈𝐶0−∞ )
𝑙
+32%
2
0
0
20
40
60
80
100
Time [h]
120
140
500 510
11
12. Institute of Occupational, Social-,
and Environmental Medicine
Summary and Conclusions I
Uptake of permethrin from clothing and its elimination from
the body can be tracked well by biomonitoring
Maximum of excretion 8 to 16h after termination of wearing
First void urine of the day following wearing best reflects
internal exposure
Exceedance of reference value in 50% of the study subjects
even after one-time exposure
Half-lifes of about 30h and elimination of ≥ 90% within 144h in
line with dermal uptake of permethrin[2]
[2]
Tomalik-Scharte et al., Eur J Clin Pharmacol, 61: 399 (2005)
12
13. Institute of Occupational, Social-,
and Environmental Medicine
Summary and Conclusions II
According to long half-life, accumulation of permethrin can be
expected in case of daily use of respective clothing at work
Internal exposure clearly dependent on wearing conditions
with increase of exposure by hot and humid climate and/or
physical workload
Possible explanation(s):
Increased release of permethrin from garment due to higher
temperature and/or sweat
Enhanced dermal uptake due to increased dermal perfusion and
maceration of stratum corneum
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14. Institute of Occupational, Social-,
and Environmental Medicine
Thank you very much for your attention!
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15. Institute of Occupational, Social-,
and Environmental Medicine
Ratio trans-DCCA / cis-DCCA
Initial ratio trans-/ cisPermethrin
in garments:
3:1
15
16. Institute of Occupational, Social-,
and Environmental Medicine
Producer of Clothing and Metabolite Excretion
DCCA in urine (mean conc.)
Mittlere Konzentation DCCA im Urin [µg/l]
25
Hersteller A
Producer A
Producer B
Hersteller B
21.5 µg/l
20
Producer A
AUC:
203 µg/l*h
t1/2:
41,4 h
15
Producer B
AUC:
1098 µg/l*h
t1/2:
29,9 h
10
5
3.5 µg/l
0 8
20
40
60
80
100
120
140
500 510
Zeitpunkt der Probenahme [h]
Time [h]
16