10.4 rossbach

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



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]

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)



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, US-

EPA: “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 [3] World Health Organisation (WHO)/Food and Agriculture Organization (FAO) Pesticide residues in food 1999

Evaluations Part II - Toxicology: Permethrin, 1999



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



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



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:

Timespan between repeated wearing of clothing under

differing conditions: at least 3 weeks

6

time from beginning of wearing [h] 0 20 40 60 80 100 120 140 500

Zeit ab Tragebeginn [h]

0 8 16 24 32 40 48 72 96 120 144 504

spot urine sample

0 20 40 60 80 100 120 140 500


0 20 40 60 80 100 120 140 500


8h urine sample “wearing period”



Metabolism scheme of permethrin (simplified)

Analytical method[4]

7

OO

O

Cl

Cl

OOH

R

O

Cl

ClOH

O

OH

Cl

Cl OOH

O

R

cis/trans permethrin (mixture of isomers)

trans-DCCA

cis-DCCA 3-PBA

+

Determination of Internal Exposure

Urine sample (10 ml)

Acidic hydrolysis

pH-controlled liquid/liquid

extraction

Derivatization

Analysis by

gas chromatography/

tandem mass spectrometry

(GC/MS-MS)

[4] according to Schettgen et al., J. Chrom. B, 778: 121 (2002)



Time Curve of DCCA-Excretion

8

maximum average excretion: 12,1 µg/l

maximum

mean

minimum

period of wearing

„reference value“

general population[4]

[4] German Federal Environmental Agency, Bundesgesundheitsbl. Gesundheitsforsch. Gesundheitsschutz, 48: 1187 (2005)

Pooled analysis of “wearing conditions” I to III

0 8 20 40 60 80 100 120 140 500 510

0.01

0.1

1

10

100

DC

CA

in u

rine [

µg/l]

Time [h]



0 8 20 40 60 80 100 120 140 500 510

0.1

1

10

wearing condition

I

II

III

DC

CA

in

uri

ne (

me

an

co

nc.)

[µ

g/l]

Time [h]

Time Curve of DCCA-Excretion

9

period of wearing

„reference value“

general population[4]

[4] German Federal Environmental Agency, Bundesgesundheitsbl. Gesundheitsforsch. Gesundheitsschutz, 48: 1187 (2005)

Separate analysis of “wearing condition” I to III

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%)



0 8 20 40 60 80 100 120 140 500 510

0.1

1

10

wearing condition

I

II

III

DC

CA

in

uri

ne (

mean c

onc.)

[µ

g/l]

Time [h]

Elimination Half-lifes

10

t1/2cond I : 36,2 h

t1/2cond II : 30,9 h

t1/2cond III : 30,0 h

Calculation by linear regression, regarding samples from 20 to 144 h from

beginning of wearing



Comparison of Excreted Amounts

11

0 20 40 60 80 100 120 140 500 510

0

2

4

6

8

10

12

14

16wearing condition

I

II

III

DC

CA

in

uri

ne (

me

an

co

nc.)

[µ

g/l]

Time [h]

+32%

+72%

𝐴𝑈𝐶0−144𝑐𝐼 = 𝟒𝟖𝟐

µ𝑔 ∙ ℎ

𝑙 (= 0.91 ∙ 𝐴𝑈𝐶0−∞)

𝐴𝑈𝐶0−144𝑐𝐼𝐼 = 𝟔𝟑𝟒

µ𝑔 ∙ ℎ

𝑙 (= 0.94 ∙ 𝐴𝑈𝐶0−∞)

𝐴𝑈𝐶0−144𝑐𝐼𝐼𝐼 = 𝟖𝟑𝟏

µ𝑔 ∙ ℎ

𝑙 (= 0.96 ∙ 𝐴𝑈𝐶0−∞)

Comparison of Area Under the Curves (AUC) resulting for different wearing

conditions



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]

12 [2] Tomalik-Scharte et al., Eur J Clin Pharmacol, 61: 399 (2005)



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

Thank you very much for your attention!



Ratio trans-DCCA / cis-DCCA

15

Initial ratio trans-/ cis-

Permethrin

in garments:

3:1



Producer of Clothing and Metabolite Excretion

16

0 8 20 40 60 80 100 120 140 500 510

5

10

15

20

25 Hersteller A

Hersteller B

Mittle

re K

onze

nta

tio

n D

CC

A im

Uri

n [

µg

/l]

Zeitpunkt der Probenahme [h]

Producer A

AUC: 203 µg/l*h

t1/2: 41,4 h

Producer B

AUC: 1098 µg/l*h

t1/2: 29,9 h

21.5 µg/l

3.5 µg/l

DC

CA

in u

rine (

mean c

on

c.)

Time [h]

Producer A

Producer B

10.4 rossbach

Health & Medicine

use of permethrin

elimination of permethrin

environmental health

environmental medicineuptake

time h

repeated wearing of

h urine sample0

urine samples