The wash-in effect and its significance for mass casualty decontamination

Figures & data

Table 1. Combined results of the literature searches

Reference	Model and summary of study	Evidence of the wash-in effect	Proposed mechanism(s) by authors
Brand et al. 2007	An ex vivo (mouse skin) assessment of altered herbicide skin penetration as a result of moisturization and hand washing	Washing skin with 5% SLS prior to 2,4-D exposure increases its percutaneous penetration from 43.4 ± 3.7% to 62.9 ± 9.5% (p < .01).	SC hydration effects Surfactant effects
Dalton, Graham, and Jenner 2018	An in vitro (porcine skin) diffusion cell assessment of VX penetration through skin in the presence of water	Penetration rates of 10 µl neat VX measured through wetted skin (86 ± 52 µg cm^−2 h^−1) between 1 and 3 h were significantly (p < .05) higher than through dry skin (19 ± 23 µg cm^−2 h^−1).	Physical effects Physicochemical effects
Forsberg et al. 2020	An in vitro (human skin) assessment of soap water and water decontamination of TICs and CWA simulants	An unquantified temporary increase in the penetration rate of 10 µl methyl salicylate through skin occurred directly after washing with either water or soapy water. An increase for 2-butoxyethanol was only observed after soapy water decontamination.	SC hydration effects Surfactant effects pH effects
Lademann et al. 2011	A human study into dry vs wet decontamination and their impact on follicular penetration	Using tape strips to determine depth of penetration, octylmethoxycinnamate was detected more deeply into the skin by washing (~7 cell layers) than by decontamination with dry absorbent materials (~ 3 cell layers).	Physical effects
Loke et al. 1999	An in vitro (human skin) study into stratum corneum hydration induced chemical penetration by various wet decontamination interventions	Wet decontamination conducted at 05h and 1h enhanced the penetration rate of diethyl malonate through skin in the immediate 2 h following decontamination when compared to no-decontamination control. A mean penetration rate enhancement of 105.55 µg h^−1 was displayed when decontaminating skin with water at 1 h over the control.	SC hydration effects Physical effects
Matar et al. 2016	An in vitro (porcine skin) evaluation of a range of decontamination products on the removal of methyl salicylate	Five water-containing products enhanced the rate and amount of penetration of methyl salicylate through skin. Over a no-decontamination control penetration of 2.5 ± 1.2%, diphoterine increased receptor fluid percentage to 6.2 ± 3.4% while baby wipes increased percentage up to 10.1 ± 5.5% over a 24 h period.	SC Hydration effects Surfactant effects
Misik et al. 2012	An in vitro (porcine skin) assessment of decontamination procedures on the penetration of paraoxon.	The penetration of paraoxon through wet skin was significantly (p = .04) higher than through dry skin, with no significant difference between dry, cold and warm skin. After 24h on dry skin, skin permeation of paraoxon was four times higher after a 3 min shower, and 60% higher after a 30s shower than controls.	Surfactant effects Physical effects In vitro artifact
Moody and Nadeau 1993	An in vivo/in vitro (mouse, rat, Guinea pig, pig, human, and tissue culture skin) comparison study into the dermal penetration of DEET.	Unquantified temporal increases in penetration rates were seen for rat, Guinea pig, pig and Testskin, but not in human skin. The temporal increase occurs following a soap water wash at 24h. No in vivo wash-in effect was identified.	Surfactant effects
Moody and Nadeau 1994	An in vivo/in vitro (rat, Guinea pig, pig, human, and tissue culture skin) comparison study into the dermal penetration of diazinon.	Unquantified temporal increases in penetration rates of diazinon were seen for rat, Guinea pig, pig, human and Testskin skin following a soap water wash at 24h, however penetration over time is only provided for human and Testskin data. No in vivo wash-in effect identified.	Surfactant effects
Moody and Nadeau 1997	An in vivo/in vitro (rat, Guinea pig, and human skin) comparison study into the dermal penetration of 2,4-D	A prominent peak in the amount of 2,4-D dermal penetration was seen for each skin at 26h post exposure, 2h after a 24h soap water wash. Following the temporal peak, increased rates of penetration did not continue to decline appreciably, remaining above baseline levels. No in vivo wash-in effect identified.	SC hydration effects Surfactant effects pH effects In vitro artifact
Moody, Nadeau, and Chu 1994	An in vivo/in vitro (rat, Guinea pig, pig, human, and tissue-cultured skin) comparison study into the dermal penetration of DDT.	Unquantified temporal increases in penetration rate of DDT were seen for rat and human skin following a soap water wash at 24h. No in vivo wash-in effect identified.	Surfactant effects Physical effects
Moody, Nadeau, and Chu 1995	An in vivo/in vitro (rat, Guinea pig, pig, and human skin) comparison study into the dermal penetration of DEET.	Up to a 32-fold increase in DEET penetration was seen in vitro for each skin at 26h, 2h post-water wash. No in vivo wash-in effect identified.	Surfactant effects
Thors et al. 2020	An in vitro (human skin) comparison between RSDL and wet decontamination in the removal of VX.	A significant (p < .05) but unquantified increase in maximum penetration rate of VX through skin was seen 1.5h following soapy water decontamination when compared with no-decontamination control. The cumulative penetrated amount of VX was also significantly (p < .05) increased when using soapy water decontamination (122.4 ± 22.3 µg cm^−2) compared to the control without decontamination (56.0 ± 6.7 µg cm^−2).	SC hydration effects Surfactant effect Physicochemical effects
Thors, Wigenstam 2021	An in vitro (human skin) comparison between RSDL and wet decontamination in the degradation of VX on and within skin.	Soapy water decontamination caused a significant (p < .05) increase in the amount of VX penetration through skin (0.87 ± 0.18 µg cm^−2) compared to no-decontamination control (0.26 ± 0.07 µg cm^−2), but significantly (p < .05) decreased agent amounts found within the stratum corneum.	Surfactant effects
Thors, Wästerby 2021	An in vitro (human skin) comparison between RSDL and wet decontamination on the removal and degradation of VX on human skin under varying cold environmental conditions.	Following application of 10 µl VX to skin and soapy water decontamination at room temperature, a significant (P < .001) increase in cumulative amounts penetrated was seen compared to no-decontamination controls. When this was repeated at −5°C and −15°C ambient air temperatures however, cumulative penetration did not significant differ from no decontamination controls.	Physical effects
Wester, Noonan, and Maibach 1977	An in vivo (Rhesus monkey) determination of hydrocortisone penetration as a single or multiple dose application, with and without washing.	A significantly higher (p < .05) percentage dose of hydrocortisone was excreted between 0–24h in soapy water wash condition (0.17%) when compared against the no wash control (0.06%).	SC hydration effects
Yousef et al. 2017	An in vitro (human skin) study into hydration enhanced dermal penetration of salicylates.	Following application of both neat and dilute solutions of ethyl, methyl and glycol salicylate to hydrated or dry skin, enhancements in rates of epidermal penetration between 1.95–10 fold (neat) and 1.98–2.32 fold (solutions) were observed.	SC hydration effects In vitro artifact
Zhu et al. 2015	An in vitro (human skin) study to identify the wash-in effect by measuring the penetration of four chemicals at varying levels of skin hydration.	A significant, cumulative enhanced penetration of paraoxon was reported through highly hydrated skin, (p = .001) after a soap water wash (3.1 ± 1.2%) compared to the non-wash control (1.2 ± 0.2%) (n = 4). The cumulative amount of benzoic acid that penetrated was lower when washed, but the peak dose 30 min post wet decontamination is around 3-fold higher than the non-wash control. No wash-in effect was seen for clonidine or hydroquinone.	SC hydration effects Physicochemical effects

Table 2. Each identified study listed by the proposed wash-in effect mechanism

Proposed wash-in effect mechanism by author	Study
SC hydration effects	Brand et al. 2007 Forsberg et al. 2020 Loke et al. 1999 Matar et al. 2016 Moody and Nadeau 1997 Thors et al. 2020 Wester, Noonan, and Maibach 1977 Yousef et al. 2017 Zhu et al. 2015
Physical effects	Dalton, Graham, and Jenner 2018 Lademann et al. 2011 Loke et al. 1999 Misik et al. 2012 Moody, Nadeau, and Chu 1994 Thors et al. 2021a
Surfactant effects	Brand et al. 2007 Forsberg et al. 2020 Matar et al. 2016 Misik et al. 2012 Moody and Nadeau 1993 Moody and Nadeau 1994 Moody and Nadeau 1997 Moody, Nadeau, and Chu 1994 Moody, Nadeau, and Chu 1995 Thors et al. 2020 Thors et al. 2020
Physicochemical effects	Dalton, Graham, and Jenner 2018 Thors et al. 2020 Zhu et al. 2015
pH effects	Forsberg et al. 2020 Moody and Nadeau 1997
In vitro artifacts	Misik et al. 2012 Moody and Nadeau 1997 Yousef et al. 2017

Figure 1. The PRISMA flow diagram showing the stages of screening and exclusion. From 733 unique papers, 60 full studies were assessed with 18 being included in the review.

Figure 2. A model skin diagram outlining four of the proposed mechanisms for the wash-in effect (physicochemical effect and in vitro artifact not shown as no harmonized single mechanism). 1) The effect of hydration on skin with (A) showing the swelling corneocytes causing cavitation between cells which leads to (B) pooling of water within the SC. SC hydration is also intrinsically linked with thermodynamic effects including altered diffusion of chemicals within the SC. 2) Surfactant micelles penetrate through the lipid bilayer, eventually leading to delipidation and membrane fluidization. 3) Physical effects including friction can remove external layers of the SC, compromising the barrier function and increasing penetration. Blood flow can further increase systemic absorption through rubefacient action, increasing clearance of compound within the skin. 4) Acids or bases can alter the acid mantle on the skin, compromising the skins barrier.

Table

1	Skin Absorption/	11678
2	skin penetra*.tw.	2131
3	dermal penetra*.tw.	286
4	percutaneous absor*.tw.	2079
5	skin absor*.tw.	708
6	dermal absor*.tw.	971
7	skin diffus*.tw.	119
8	dermal diffus*.tw.	23
9	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8	14169
10	enhanc*.tw.	1471408
11	9 and 10	3512
12	(skin or dermal).tw.	554169
13	(hydrat* or wash*).tw.	183811
14	12 and 13	7204
15	11 and 14	181

Table

1	“Wash-in effect”	9
2	“Wash in effect”	9
3	1 or 2	9

Brand, R. M., A. R. Charron, V. L. Sandler, and J. L. Jendrzejewski. 2007. Moisturizing lotions can increase transdermal absorption of the herbicide 2,4-dichlorophenoxacetic acid across hairless mouse skin. Cutan Ocul Toxicol 26 (1):15–23. doi:https://doi.org/10.1080/15569520601182791.

 PubMed Web of Science ®Google Scholar

Dalton, C., S. Graham, and J. Jenner. 2018. Effect of aqueous dilution on the absorption of the nerve agent VX through skin in vitro. Toxicol. in Vitro 53:121–25. doi:https://doi.org/10.1016/j.tiv.2018.08.003.

 PubMed Web of Science ®Google Scholar

Forsberg, E., L. Öberg, E. Artursson, E. Wigenstam, A. Bucht, and L. Thors. 2020. Decontamination efficacy of soapy water and water washing following exposure of toxic chemicals on human skin. Cutan Ocul Toxicol 39 (2):134–42. doi:https://doi.org/10.1080/15569527.2020.1748046.

 PubMed Web of Science ®Google Scholar

Lademann, J., A. Patzelt, S. Schanzer, H. Richter, I. Gross, K. H. Menting, L. Frazier, W. Sterry, and C. Antoniou. 2011. Decontamination of the skin with absorbing materials. Skin. Pharmaco.l Physiol. 24 (2):87–92. doi:https://doi.org/10.1159/000322305.

 PubMed Web of Science ®Google Scholar

Loke, W. K., S. H. U, S. K. Lau, J. S. Lim, G. S. Tay, and C. H. Koh. 1999. Wet decontamination-induced stratum corneum hydration–effects on the skin barrier function to diethylmalonate. J. Appl. Toxicol. 19 (4):285–90. doi:https://doi.org/10.1002/(SICI)1099-1263(199907/08)19:4<285::AID-JAT580>3.0.CO;2-X.

 PubMed Web of Science ®Google Scholar

Matar, H., A. Guerreiro, S. A. Piletsky, S. C. Price, and R. P. Chilcott. 2016. Preliminary evaluation of military, commercial and novel skin decontamination products against a chemical warfare agent simulant (methyl salicylate). Cutan Ocul Toxicol 35 (2):137–44. doi:https://doi.org/10.3109/15569527.2015.1072544.

 PubMed Web of Science ®Google Scholar

Misik, J., R. Pavlikova, D. Josse, D. Josse, and D. Josse. 2012. In vitro skin permeation and decontamination of the organophosphorus pesticide paraoxon under various physical conditions – Evidence for a wash-in effect. Toxicol. Mech. Methods 22 (7):520–25. doi:https://doi.org/10.3109/15376516.2012.686535.

 PubMed Web of Science ®Google Scholar

Moody, R. P., and B. Nadeau. 1993. An automated in vitro dermal absorption procedure: III. In vivo and in vitro comparison with the insect repellent N,N-diethyl-m-toluamide in mouse, rat, Guinea pig, pig, human and tissue-cultured skin. Toxicol. in Vitro 7 (2):167–76. doi:https://doi.org/10.1016/0887-2333(93)90128-R.

 PubMed Web of Science ®Google Scholar

Moody, R. P., and B. Nadeau. 1994. In vitro dermal absorption of pesticides: IV. In vivo and in vitro comparison with the organophosphorus insecticide diazinon in rat, Guinea pig, pig, human and tissue-cultured skin. Toxicol. in Vitro 8 (6):1213–18. doi:https://doi.org/10.1016/0887-2333(94)90111-2.

 PubMed Web of Science ®Google Scholar

Moody, R. P., and B. Nadeau. 1997. In vitro dermal absorption of two commercial formulations of 2,4-dichlorophenoxyacetic acid dimethylamine (2,4-D amine) in rat, Guinea pig and human skin. Toxicol. in Vitro 11 (3):251–62. doi:https://doi.org/10.1016/S0887-2333(97)00013-1.

 PubMed Web of Science ®Google Scholar

Moody, R. P., B. Nadeau, and I. Chu. 1994. In vitro dermal absorption of pesticides: VI. In vivo and in vitro comparison of the organochlorine insecticide DDT in rat, Guinea pig, pig, human and tissue-cultured skin. Toxicol. in Vitro 8 (6):1225–32. doi:https://doi.org/10.1016/0887-2333(94)90113-9.

 PubMed Web of Science ®Google Scholar

Moody, R. P., B. Nadeau, and I. Chu. 1995. In vitro dermal absorption of N,N-diethyl-m-toluamide (DEET) in rat, Guinea pig, and human skin. Vitro Toxicology 8:263–75.

 Google Scholar

Thors, L., E. Wigenstam, J. Qvarnström, L. Hägglund, and A. Bucht. 2020. Improved skin decontamination efficacy for the nerve agent VX. Chem. Biol. Interact. 325:109135. doi:https://doi.org/10.1016/j.cbi.2020.109135.

 PubMed Web of Science ®Google Scholar

Thors, L., P. Wästerby, E. Wigenstam, A. Larsson, L. Öberg, and A. Bucht. 2021a. Do cold weather temperatures affect the efficacy of skin decontamination? J. Appl. Toxicol.Early View. doi:https://doi.org/10.1002/jat.4265.

 Google Scholar

Wester, R. C., P. K. Noonan, and H. I. Maibach. 1977. Frequency of application on percutaneous absorption of hydrocortisone. Arch. Dermatol. 113 (5):620–22. doi:https://doi.org/10.1001/archderm.1977.01640050080011.

 PubMedGoogle Scholar

Yousef, S., Y. Mohammed, S. Namjoshi, J. Grice, W. Sakran, and M. Roberts. 2017. Mechanistic evaluation of hydration effects on the human epidermal permeation of salicylate esters. AAPS J. 19 (1):180–90. doi:https://doi.org/10.1208/s12248-016-9984-0.

 PubMed Web of Science ®Google Scholar

Zhu, H., E. C. Jung, C. Phuong, X. Hui, and H. Maibach. 2015. Effects of soap-water wash on human epidermal penetration. J. Appl. Toxicol. 36 (8):997–1002. doi:https://doi.org/10.1002/jat.3258.

 PubMed Web of Science ®Google Scholar

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.