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)
5

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
13

14. Institute of Occupational, Social-,
and Environmental Medicine
Thank you very much for your attention!
14

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