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Klingner

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    Klingner Klingner Presentation Transcript

    • Fundamentals of Dermal Exposure Thomas D. Klingner Colormetric Laboratories, Inc.
    • Understanding the Skin The skin is the largest organ of the body (20,000 cm2). The skin has two primary functions: 1. It serves as a physical barrier to infectious agents. 2. It retains moisture in the body.
    • Structure of the Skin The skin is often conceived as a brick and mortar structure. The interstitial lipids bind the corneocytes together and form a lipophilic pathway for chemical absorption into the Stratum Corneum.
    • Stratum Corneum: the initial barrier to dermal exposure Comprised of layers of keratin (dead skin cells) held together by a lipid matrix (0.01-0.06 mm thick). Membrane coating granules (MCG) produce fatty oils that retain the body’s moisture.
    • The Chemistry of Exposure Three Basic Principles Oil and water don’t mix
    • First Principle Like Dissolves Like - chemicals will migrate from a low solubility toward a high solubility environment. This principle introduces the important concept of the octanol water partition coefficient or Ko/w. Chemical solubility is characterized based on how soluble a chemical is in each phase of a 50:50 water and octanol mixture. Water (hydrophillic) and octanol (lipophillic) lie at opposite ends of the solubility spectrum. The preferential solubility in either phase determines where chemicals lie in the solubility spectrum.
    • Second Principle Concentration gradient (Ficks Law) 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.
    • Third Principle Molecular Size The lower the chemical molecular weight (MW) the more rapid diffusion will proceed. Large molecules will penetrate slowly if at all. Small grains of sand will quickly sift through a series of screens where large grains will pass through slowly or not at all. The skins corneocytes, arranged in the brick and mortar structure, slow or prevent absorption of large molecules.
    • The Process of Dermal Exposure Step 1 - initial dermal uptake The skin’s primary function is to retain water, therefore, the skin is an excellent barrier to water soluble chemicals. Oil soluble chemicals are readily soluble in the skin’s lipids and rapidly partition into the stratum corneum. The K o/w lipid solubility of the chemical determines how rapidly the chemical is absorbed into the skin. As the skin’s solvent capacity approaches saturation, the total exposed area of the skin determines the total 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+).
    • Log Kp = 2.72 + 0.71 log K o/w -0.0061 MW Potts and Guy, USEPA 1992 Chemical CAS No. MW Log K o/w Kp (cm/hr) This equation is used by the EPA Nitrophenol, 4- 4- 100027 139.1 1.91 6.1E-3 6.1E- to predict skin uptake or the permeation constant Kp of toxic Nitrophenol, 4-amino-2- 4- amino- 119346 154.1 0.96 1.1E-3 1.1E- chemicals. Nitropropane,2 79469 110 0.55 1.0E-3 1.0E- Nitroso-di-n-butylamine,n- Nitroso- di- butylamine,n- 924163 158.2 1.92 4.8E-3 4.8E- As the solubility increases (higher K o/w) Kp also increases. As the Nitroso-N-ethylurea,n- Nitroso- ethylurea,n- 759739 117.1 0.23 540.0E-6 540.0E- MW increases the Kp decreases. Nitroso-N-methylurea,n- Nitroso- methylurea,n- 684935 103.1 -0.03 430.0E-6 430.0E- Nitrosodiethanolamine,n- Nitrosodiethanolamine,n- 1116547 134 -1.58 22.0E-6 22.0E- Compare: Phenanthrene log K o/w 4.57, MW 178.2 Kp is 0.27 Nitrosodiethylamine,n- Nitrosodiethylamine,n- 55185 88 0.48 1.2E-3 1.2E- cm/hr. Nitrosodiethanolamine, Nitrosodiphenylamine,p- Nitrosodiphenylamine,p- 156105 198.2 3.5 36.0E-3 36.0E- n- log K o/w -1.58 MW 134.0 Kp Nitrosomethylvinylamine,n- Nitrosomethylvinylamine,n- 4549400 86.1 0 570.0E-6 570.0E- 0.000022 cm/hr. cm/hr. Nitrosomorpholine, n- n- 59892 116.1 -0.44 180.0E-6 180.0E- The Phenanthrene will penetrate Nitrosonornicotine,n- Nitrosonornicotine,n- 16543558 177.2 0.03 170.0E-6 170.0E- the skin1000x faster. Nitrosopiperidine, n- n- 100754 350.3 0.36 25.0E-6 25.0E- Nonanol 143088 144 3.47 73.0E-3 73.0E- Octanol 111875 130 2.97 39.0E-3 39.0E- Parathion 56382 291 3.83 17.0E-3 17.0E- PCB-chlorobiphenyl, 4- PCB- 4- 2051629 292 6.5 1.3E+0 PCB-hexachlorobiphenyl PCB- 26601649 361 6.72 710.0E-3 710.0E- Pentachloronitrobenzene 82688 295.3 4.64 59.0E-3 59.0E- Pentachloropenol 87865 266.4 5.86 650.0E-3 650.0E- Pentanol 71410 88 1.56 7.1E-3 7.1E- Pentanone, 4-methyl-2- 4- methyl- 108101 100 1.19 3.3E-3 3.3E- Phenanthrene 85018 178.2 4.57 270.0E-3 270.0E- Phenol 108952 94 1.46 5.5E-3 5.5E-
    • Step 2 - Systemic Uptake Chemical Warfare Agents (CWA’s) have a low molecular weight, are moderately lipophillic and highly toxic. To be effective systemic toxins CWA’s must also demonstrate some degree of water solubility i.e. midrange K o/w, to partition into the blood stream. More lipophilic chemicals rapidly saturate the stratum corneum lipids capacity, but slowly partition into the hydrophillic bloodstream limiting systemic toxicity. As long as the skin remains dry, lipophilic chemicals remain more soluble in the skin lipids limiting systemic absorption.
    • The Skin Depot – wash-in effect Washing with soap and water hydrates the skin and may worsen exposures to lipophilic chemicals. The chart below shows what happened after washing with soap and water at the 24 hr. mark for four exposures. The irony – soap and water is effective for water soluble chemicals. Water soluble chemicals tend to be poorly absorbed via healthy and intact skin. Washing the skin with soap and water or solvents may actually enhance absorption of lipophilic chemicals. R. Moody, Toxic. In Vitro,8; 1225 1994 0.07 0.06 0.05 1 % 0.04 2 Permeation 0.03 3 0.02 4 0.01 0 4 8 12 16 20 24 26 28 32 36 40 44 48 Time (Hrs.) 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.
    • Comparison of enhancement effect of decontamination solution on rate of percutaneous penetration of diethylmalonate remaining in skin samples that 300 were decontaminated 1 hour post exposure. Loke et. al, 1999 250 control Decontamination Mean enhancement in 200 1/4 hr. decon Solution penetration rate % 2% (w/v)anionic surfactant 141.19 2% (w/v) cationic surfactant 138.03 150 1/2 hr. decon 2% (w/v) non-ionic surfactant 135.32 de-ionized water hypotonic solution 105.55 100 1 hr. decon 0.9% (w/v)saline isotonic solution 71.27 9 % (w/v) saline hypertonic solution 23.17 50 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 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. The CWA 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.
    • Like Dissolves Like 60% 50% 4 hours 40% 30% 20% 8 hours 10% 0% water 50% polyglycol corn oil soap (D-TAM) % of MDI dose remaining in skin This study compared the ability of water, 50% soap and water, a polyglycol based cleanser and corn oil (control) to minimize absorption of isocyanate (MDI) into the skin. The data show that corn oil and the polyglycol based cleanser are more effective than water or soap and water in limiting the transfer of MDI into the skin. These results are consistent with the miscibility of MDI in corn oil and polyglycol. Ronald C. Wester et al. In Vivo Evaluation of MDI Skin Decontamination Procedures. Presented September 1998, Polyurethane Expo. Even after 8 hours, less than 10% of the applied dose entered the skin when decontaminated with non-aqueous HMW solvents. Water alone drove over 50% of the dose into the skin.
    • Solubility in Skin Decontamination Solvents A Rational Approach to Skin Decontamination,T. Buckley, Johns Hopkins Univ., M. Dellarco, USEPA, T. Klingner, CLI Laboratories, AIHA Conference 2001 Comparison of Saturation 100% 90% 80% Water 70% 10% soap Solublity 60% D-TAM 50% 40% Glycol 30% D-TAM Oil 20% 10% 0% methylenedianiline chlorpyrifos pentachlorophenol benzo-a-pyrene log ko/w1.59** log k o/w 4.7*** log k o/w 5.86** log k o/w 6.5** *Relative to solvent with maximum solubility; maximum solubility was not always achieved ** solubility determined spectrophotometrically ***solubility determined by visual inspection of mass dissolving in solution Premise: The more soluble the contaminant is in the decontamination agent the more effective the decontamination process.
    • Skin Decontamination Selection Guide for D-TAM Skin Cleanser and D-TAM Safe Solvent Log K o/w 0 3.5 8.0 Soap and Water D-TAM™ Skin D-TAM™ Safe Cleanser (Peg Based) Solvent (plant oil based) TDI Phenol Aldrin Benzo-a-pyrene Formaldehyde Aniline Di-nitro-Toluene MDI Lindane Penatchlorphenol Propanol Acetone PCBs Trinitrobenzene Malathion DDT Hydrazine Dichlorethane Diesel Oil 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 old This worker was accidentally This worker collapsed at work This worker also collapsed after wearing sprayed with parathion during after receiving the freshly laundered the re-laundered uniform. The connection the manufacturing process. The uniform that was previously was made with the earlier contamination and contaminated uniform was removed contaminated. There was no it was destroyed. No further incidences and inadvertently sent to be obvious exposure connected to this occurred. Patient recovered in hospital. laundered rather than destroyed. and the uniform was removed Patient recovered in hospital. and sent to be laundered. Patient recovered in hospital.
    • Re-use of PPC; Potential Exposure to Pesticides Garrod, Phillips, Pemberton, Amer. Occup. Hyg., Vol 45, No.1, 2001 38% of agricultural workers using unapproved disposable gloves showed positive exposure to hands. 95% of workers who re-used chemical protective gloves (protection factor 20X) had positive exposure. The re-use of contaminated PPC can result in significant unanticipated exposure. Proper decontamination of PPC can 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