Fundamentals of Fundamentals of Dermal ExposureDermal ExposureThomas D. KlingnerThomas D. KlingnerColormetric Laboratories, Inc.Colormetric Laboratories, Inc.

Understanding the SkinUnderstanding the Skin

The skin is the largest organ of the body The skin is the largest organ of the body (20,000 cm(20,000 cm22).).The skin has two primary functions: The skin has two primary functions:

1. It serves as a physical barrier to 1. It serves as a physical barrier to infectious agents.infectious agents.

2. It retains moisture in the body. 2. It retains moisture in the body.

Structure of the SkinStructure of the Skin

The skin is often conceived asa brick and mortar structure. Theinterstitial lipids bind the corneocytes together and form a lipophilic pathway for chemicalabsorption into the Stratum Corneum.

Stratum Corneum:Stratum Corneum:the initial barrier to dermal the initial barrier to dermal exposureexposure

Comprised of layers of keratin (dead skin Comprised of layers of keratin (dead skin cells) held together by a lipid matrix cells) held together by a lipid matrix (0.01(0.01--0.06 mm thick).0.06 mm thick).Membrane coating granules (MCG) Membrane coating granules (MCG) produce fatty oils that retain the bodyproduce fatty oils that retain the body’’s s moisture.moisture.

The Chemistry of The Chemistry of ExposureExposureThree Basic PrinciplesThree Basic Principles

Oil and water donOil and water don’’t mixt mix

First PrincipleFirst Principle

Like Dissolves LikeLike Dissolves Like

-- chemicals will migrate from a low solubility toward a high chemicals will migrate from a low solubility toward a high solubility environment.solubility environment.

This principle introduces the important concept of the octanol wThis principle introduces the important concept of the octanol water partition ater partition coefficient or Ko/w. Chemical solubility is characterized based coefficient or Ko/w. Chemical solubility is characterized based on how on how soluble a chemical is in each phase of a 50:50 water and octanolsoluble a chemical is in each phase of a 50:50 water and octanol mixture. mixture. Water (hydrophillic) and octanol (lipophillic) lie at opposite eWater (hydrophillic) and octanol (lipophillic) lie at opposite ends of the nds of the solubility spectrum.solubility spectrum.

The preferential solubility in either phase determines where cheThe preferential solubility in either phase determines where chemicals lie in micals lie in the solubility spectrum.the solubility spectrum.

Concentration gradientConcentration gradient (Ficks Law)(Ficks Law)

Second Principle

Chemicals will diffuse from a high concentration toward a lower concentration.

This occurs in air and in the skin. Spilled solvent evaporates contaminating the air in a room to saturation. A drop of chemical on the skin will permeate into the skin lipids until the skins solvent capacity is saturated. This is the skin depot capacity.

Molecular SizeMolecular Size

The lower the chemical molecular weight (MW) the more The lower the chemical molecular weight (MW) the more rapid diffusion will proceed. Large molecules will rapid diffusion will proceed. Large molecules will penetrate slowly if at all.penetrate slowly if at all.

Small grains of sand will quickly sift through a series of Small grains of sand will quickly sift through a series of screens where large grains will pass through slowly or screens where large grains will pass through slowly or not at all. The skins corneocytes, arranged in the brick not at all. The skins corneocytes, arranged in the brick and mortar structure, slow or prevent absorption of and mortar structure, slow or prevent absorption of large molecules.large molecules.

Third Principle

The Process of Dermal The Process of Dermal ExposureExposure

Step 1 Step 1 -- initial dermal uptakeinitial dermal uptakeThe skinThe skin’’s primary function is to retain water, therefore, s primary function is to retain water, therefore, the skin is an excellent barrier to water soluble the skin is an excellent barrier to water soluble chemicals.chemicals.Oil soluble chemicals are readily soluble in the skinOil soluble chemicals are readily soluble in the skin’’s s lipids and rapidly partition into the stratum corneum.lipids and rapidly partition into the stratum corneum.

The K o/w lipid solubility of the chemical determines how The K o/w lipid solubility of the chemical determines how rapidly the chemical is absorbed into the skin. As the rapidly the chemical is absorbed into the skin. As the skinskin’’s solvent capacity approaches saturation, the total s solvent capacity approaches saturation, the total exposed area of the skin determines the total exposed area of the skin determines the total exposure.exposure.

A chemical’s ability to penetrate the outer barrier of the skin (stratum corneum) depends on two physiochemical properties.

Increasing molecular weight and size is a conflicting factor in skin penetration. Thus, where compounds may become more lipophilic with increasing size, the ability of these compounds to diffuse through the intercellular spaces is reduced.

With solubility remaining constant, a low molecular weight chemical (L.M.W. 100) will penetrate 100x to 1000x faster than a high molecular chemical (H.M.W. 400+).

5.5E5.5E--331.461.469494108952108952PhenolPhenol

270.0E270.0E--334.574.57178.2178.28501885018PhenanthrenePhenanthrene

3.3E3.3E--331.191.19100100108101108101Pentanone, 4Pentanone, 4--methylmethyl--22--

7.1E7.1E--331.561.5688887141071410PentanolPentanol

650.0E650.0E--335.865.86266.4266.48786587865Pentachloropenol Pentachloropenol

59.0E59.0E--334.644.64295.3295.38268882688Pentachloronitrobenzene Pentachloronitrobenzene

710.0E710.0E--336.726.723613612660164926601649PCBPCB--hexachlorobiphenyl hexachlorobiphenyl

1.3E+01.3E+06.56.529229220516292051629PCBPCB--chlorobiphenyl, 4chlorobiphenyl, 4--

17.0E17.0E--333.833.832912915638256382ParathionParathion

39.0E39.0E--332.972.97130130111875111875OctanolOctanol

73.0E73.0E--333.473.47144144143088143088Nonanol Nonanol

25.0E25.0E--660.360.36350.3350.3100754100754Nitrosopiperidine, nNitrosopiperidine, n--

170.0E170.0E--660.030.03177.2177.21654355816543558Nitrosonornicotine,nNitrosonornicotine,n--

180.0E180.0E--66--0.440.44116.1116.15989259892Nitrosomorpholine, nNitrosomorpholine, n--

570.0E570.0E--660086.186.145494004549400Nitrosomethylvinylamine,nNitrosomethylvinylamine,n--

36.0E36.0E--333.53.5198.2198.2156105156105Nitrosodiphenylamine,pNitrosodiphenylamine,p--

1.2E1.2E--330.480.4888885518555185Nitrosodiethylamine,nNitrosodiethylamine,n--

22.0E22.0E--66--1.581.5813413411165471116547Nitrosodiethanolamine,nNitrosodiethanolamine,n--

430.0E430.0E--66--0.030.03103.1103.1684935684935NitrosoNitroso--NN--methylurea,nmethylurea,n--

540.0E540.0E--660.230.23117.1117.1759739759739NitrosoNitroso--NN--ethylurea,nethylurea,n--

4.8E4.8E--331.921.92158.2158.2924163924163NitrosoNitroso--didi--nn--butylamine,nbutylamine,n--

1.0E1.0E--330.550.551101107946979469Nitropropane,2Nitropropane,2

1.1E1.1E--330.960.96154.1154.1119346119346Nitrophenol, 4Nitrophenol, 4--aminoamino--22--

6.1E6.1E--331.911.91139.1139.1100027100027Nitrophenol, 4Nitrophenol, 4--This equation is used by the EPA This equation is used by the EPA to to predictpredict skin uptake or the skin uptake or the permeation constant Kp of toxic permeation constant Kp of toxic chemicals.chemicals.

As the solubility increases (higher As the solubility increases (higher K o/w) Kp also increases. As the K o/w) Kp also increases. As the MW increases the Kp decreases. MW increases the Kp decreases.

Compare: Compare: Phenanthrene log K Phenanthrene log K o/w 4.57, MW 178.2 o/w 4.57, MW 178.2 KpKp is 0.27 is 0.27 cm/hr.cm/hr. Nitrosodiethanolamine, Nitrosodiethanolamine, nn-- log K o/w log K o/w --1.58 MW 134.0 Kp 1.58 MW 134.0 Kp 0.000022 cm/hr0.000022 cm/hr. .

The The PhenanthrenePhenanthrene will penetrate will penetrate the skin1000x faster.the skin1000x faster.

Kp (cm/hr)Kp (cm/hr)Log K o/wLog K o/wMWMWCAS No.CAS No.ChemicalChemical

Log Kp = 2.72 + 0.71 log K o/w Log Kp = 2.72 + 0.71 log K o/w --0.0061 MW Potts and Guy, USEPA 19920.0061 MW Potts and Guy, USEPA 1992

Step 2 Step 2 -- Systemic UptakeSystemic UptakeChemical Warfare Agents (CWAChemical Warfare Agents (CWA’’s) have a low molecular weight, s) have a low molecular weight,

are moderately lipophillic and highly toxic. To be effective are moderately lipophillic and highly toxic. To be effective systemic toxins CWAsystemic toxins CWA’’s must also demonstrate some degree of s must also demonstrate some degree of water solubility i.e. midrange K o/w, to partition into the bloowater solubility i.e. midrange K o/w, to partition into the blood d stream. stream.

More lipophilic chemicals rapidly saturate the stratum corneum More lipophilic chemicals rapidly saturate the stratum corneum lipids capacity, but slowly partition into the hydrophillic lipids capacity, but slowly partition into the hydrophillic bloodstream limiting systemic toxicity. As long as the skin bloodstream limiting systemic toxicity. As long as the skin remains dry, lipophilic chemicals remain more soluble in the skiremains dry, lipophilic chemicals remain more soluble in the skin n lipids limiting systemic absorption.lipids limiting systemic absorption.

Washing with soap and water hydrates the skin and may worsen expWashing with soap and water hydrates the skin and may worsen exposures to lipophilic osures to lipophilic chemicals. The chart below shows what happened after washing witchemicals. The chart below shows what happened after washing with soap and water at the h soap and water at the 24 hr. mark for four exposures.24 hr. mark for four exposures.The irony The irony –– soap and water is effective for water soluble chemicals. Water soap and water is effective for water soluble chemicals. Water soluble chemicals soluble chemicals tend to be poorly absorbed via healthy and intacttend to be poorly absorbed via healthy and intact skin.skin.

The Skin Depot The Skin Depot –– washwash--in in effecteffect

Washing the skin with soap and water or solvents may actually enWashing the skin with soap and water or solvents may actually enhance absorption of hance absorption of lipophilic chemicals. R. Moody, Toxic. In Vitro,8; 1225 1994lipophilic chemicals. R. Moody, Toxic. In Vitro,8; 1225 1994

00.010.020.030.040.050.060.07

4 8 12 16 20 24 26 28 32 36 40 44 48

Time (Hrs.)

% Permeation

1234

DDT was applied to the skin and the percentage of permeation into the bloodstream measured. The excess lipophillic DDT (K o/w 6.36) was washed from the skin after 24 hrs. and the percentage penetrating the bloodstream increased by 5 fold.

300300

250250 controlcontrol

200200 1/4 hr. decon1/4 hr. decon

150150 1/2 hr. decon1/2 hr. decon

100100 1 hr. decon1 hr. decon

5050

001 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 191 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 2520 21 22 23 24 25

Decontamination Decontamination Mean enhancement Mean enhancement inin

SolutionSolution penetration rate % penetration rate % 2% (w/v)anionic surfactant2% (w/v)anionic surfactant 141.19141.192% (w/v)2% (w/v) cationic surfactantcationic surfactant 138.03138.03

2% (w/v)2% (w/v) nonnon--ionic surfactantionic surfactant 135.32135.32dede--ionized water hypotonic solutionionized water hypotonic solution 105.55105.550.9% (w/v)saline isotonic solution0.9% (w/v)saline isotonic solution 71.2771.279 % (w/v) saline hypertonic solution9 % (w/v) saline hypertonic solution 23.1723.17

Comparison of enhancement effect of decontamination solution on rate of percutaneous penetration of diethylmalonate remaining in skin samples that were decontaminated 1 hour post exposure. Loke et. al, 1999

Time is the crucial factor in decontamination.Diethylmalonate, a nerve agent simulant, was washed from the skin after increasing time intervals of ¼ to ½ hrs. After ½ hr. decontamination with soap and water or water increased systemic absorption vs. the control (no decontamination). Nerve agents require a certain effective dose to be absorbed. It is possible that controls may have lived and those decontaminated at 1 hr. would have died.

Solubility is the key.

Note: The EPA “Recognition and Management Pesticide Poisoning” 1999 recommends washing with soap and water.

The pesticide Alachlor that is lipophillic is supplied in a solvent concentrate and applied in a diluted water emulsion spray. As the Alachlor was, diluted from 20 parts water to 80 parts water, the concentration was 4x lower but the systemic absorption increased 4x. Alachlor remained more soluble in the more concentrated emulsion than in the skin.

Evaluation of compounds as barriers to dermal penetration of organophosphates using

acetylcholinesterase inhibition. Olson, Carl T. et al Toxicity Letters, 55(1991) 325-334

Ed50 Values and 95% confidence limits for acetylcholinesterase inhibition.

OP compound Time after exposure (min.) Ed50 (95% confidence limits)

No barrier PEG 540 barrier (mg/kg) (mg/kg)

TGD 30 1.90 (1.44-2.52) 1915 (0.05-8 X 107)

60 1.01 (0.81-1.26) 33.3 (11.0-100)

120 0.94 (0.710-01.23) 7.89 (5.44-11.4)

240 1.06 (0.83-1.34) 6.28 (4.96-7.95)

GD 30 0.68 (0.52-0.89) 14.4 (5.43-38.4)

60 0.56 (0.40-0.78) 6.17 (3.82-9.97)

120 0.54 (0.39-0.75) 4.39 (2.67-7.22)

240 0.49 (0.33-0.73) 1.76 (0.75-4.12)

VX 30 0.131 (0.031-0.549) 167 (0.9 x 103)

60 0.026 (0.017-0.040) 18.2 (0.055-6002)

120 0.012 (0.010-0.014) 3.38 (0.104-110)

240 0.007 (0.005-0.008) 10 (0.043-103)

A barrier of HMW polyethelene glycol (MW 540) was applied to the skin of rats before exposure to various CWA’s. TheCWA was more soluble in PEG barrier than the skin and systemic absorption was slower. For example, for VX to

achieve systemic toxicity in 30 minutes, .131 mg/Kg was effective with no barrier. With PEG, .167 mg/kg was applied to achieve the same level of toxicity. An increase of 1000x.

60%50%40%30%20%10%0%

water 50% polyglycol corn oilsoap (D-TAM)

% of MDI dose remaining in skin

8 hours

4 hours

This study compared the ability of water, 50% soap and water, a This study compared the ability of water, 50% soap and water, a polyglycol based cleanser polyglycol based cleanser and corn oil (control) to minimize absorption of isocyanate (MDIand corn oil (control) to minimize absorption of isocyanate (MDI) into the skin. The data ) into the skin. The data show that corn oil and the polyglycol based cleanser are more efshow that corn oil and the polyglycol based cleanser are more effective than water or soap fective than water or soap and water in limiting the transfer of MDI into the skin. These and water in limiting the transfer of MDI into the skin. These results are consistent with the results are consistent with the miscibility of MDI in corn oil and polyglycol.miscibility of MDI in corn oil and polyglycol.

Ronald C. Wester et al. Ronald C. Wester et al. In Vivo Evaluation of MDI Skin Decontamination ProceduresIn Vivo Evaluation of MDI Skin Decontamination Procedures. Presented . Presented September 1998, Polyurethane Expo.September 1998, Polyurethane Expo.

Even after 8 hours, less than 10% of the applied dose entered thEven after 8 hours, less than 10% of the applied dose entered the skin when decontaminated e skin when decontaminated with nonwith non--aqueous HMW solvents. Water alone drove over 50% of the dose intaqueous HMW solvents. Water alone drove over 50% of the dose into the skin.o the skin.

Like Dissolves Like

Solubility in Skin Decontamination SolventsSolubility in Skin Decontamination SolventsA Rational Approach to Skin Decontamination,T. Buckley, Johns HoA Rational Approach to Skin Decontamination,T. Buckley, Johns Hopkins Univ., M. pkins Univ., M.

Dellarco, USEPA, T. Klingner, CLI Laboratories, AIHA Conference Dellarco, USEPA, T. Klingner, CLI Laboratories, AIHA Conference 20012001Comparison of SaturationComparison of Saturation100%100%90%90%80%80%70%70%60%60%50%50%40%40%30%30%20%20%10%10%0%0%

methylenedianiline chlorpyrifos pentachlorophenolmethylenedianiline chlorpyrifos pentachlorophenol benzobenzo--aa--pyrenepyrenelog ko/w1.59** log k o/w 4.7*** log k o/w 5.86** log ko/w1.59** log k o/w 4.7*** log k o/w 5.86** log k o/w 6.5**log k o/w 6.5**

*Relative to solvent with maximum solubility; maximum solubility*Relative to solvent with maximum solubility; maximum solubility was not alwayswas not always achievedachieved** solubility determined spectrophotometrically** solubility determined spectrophotometrically***solubility determined by visual inspection of mass dissolving***solubility determined by visual inspection of mass dissolving in solutionin solution

Water

10% soap

D-TAM

Glycol

D-TAM Oil

Sol

ublit

y

Premise: The more soluble the contaminant is in the decontamination agent the more effectivethe decontamination process.

Skin Decontamination Selection Guidefor

D-TAM Skin Cleanser and D-TAM Safe Solvent

Log K o/w 0 3.5 8.0Soap and Water

Formaldehyde

Propanol

Hydrazine

Phenol

Acetone

D-TAM™ Skin

Cleanser (Peg Based)

Aniline

Di-nitro-Toluene

Trinitrobenzene

Dichlorethane

D-TAM™ Safe Solvent (plant oil based)

TDI

Benzo-a-pyrene

MDIPenatchlorphenol

PCBs

DDT

Diesel Oil

Aldrin

Lindane

Malathion

By adjusting the K o/w of the HMW D-TAM formulation effective decontamination of chemicals across the entire solubility spectrum can be achieved.

Ineffective Decontamination:

A False Sense of Security

Organophosphate poisoning from wearing a laundered uniform previously contaminated with parathion.

Clifford, N.J., Nies, A.S., JAMA 12, 1, 89 Vol 262 No 21

Case 1 Case 2 Case 3

25 year old 23 year old 18 year oldThis worker was accidentallysprayed with parathion duringthe manufacturing process. The contaminated uniform was removedand inadvertently sent to be laundered rather than destroyed.Patient recovered in hospital.

This worker collapsed at work after receiving the freshly laundereduniform that was previously contaminated. There was no obvious exposure connected to this and the uniform was removed and sent to be laundered. Patientrecovered in hospital.

This worker also collapsed after wearingthe re-laundered uniform. The connection was made with the earlier contamination and it was destroyed. No further incidences occurred. Patient recovered in hospital.

ReRe--use of PPC; Potential use of PPC; Potential Exposure to Pesticides Exposure to Pesticides Garrod, Phillips, Pemberton, Amer. Occup. Hyg., Vol 45, No.1, 20Garrod, Phillips, Pemberton, Amer. Occup. Hyg., Vol 45, No.1, 200101

38% of agricultural workers using unapproved 38% of agricultural workers using unapproved disposable gloves showed positive exposure to hands.disposable gloves showed positive exposure to hands.95% of workers who re95% of workers who re--used chemical protective used chemical protective gloves (protection factor 20X) had positive exposure.gloves (protection factor 20X) had positive exposure.

The reThe re--use of contaminated PPC can result in significant use of contaminated PPC can result in significant unanticipated exposure. Proper decontamination of PPC can unanticipated exposure. Proper decontamination of PPC can prevent these exposures.prevent these exposures.

“It is better to learn from someone else’s mistakes rather than your own.” Dear Ole Dad

• 25% of medical personnel treating victims of the Tokyo sarin terrorist attack were themselves acutely poisoned.

“Good ideas are not adopted automatically. They must be driven into practice with courageous impatience.”Admiral Hyman Rickover