Dermal Uptake of 18 Dilute Aqueous Chemicals: In Vivo Disappearance‐Method Measures Greatly Exceed In Vitro‐Based Predictions

Abstract

Average rates of total dermal uptake (Kup ) from short-term (e.g., bathing) contact with dilute aqueous organic chemicals (DAOCs) are typically estimated from steady-state in vitro diffusion-cell measures of chemical permeability (Kp ) through skin into receptor solution. Widely used ("PCR-vitro") methods estimate Kup by applying diffusion theory to increase Kp predictions made by a physico-chemical regression (PCR) model that was fit to a large set of Kp measures. Here, Kup predictions for 18 DAOCs made by three PCR-vitro models (EPA, NIOSH, and MH) were compared to previous in vivo measures obtained by methods unlikely to underestimate Kup . A new PCR model fit to all 18 measures is accurate to within approximately threefold (r = 0.91, p < 10(-5) ), but the PCR-vitro predictions (r > 0.63) all tend to underestimate the Kup measures by mean factors (UF, and p value for testing UF = 1) of 10 (EPA, p < 10(-6) ), 11 (NIOSH, p < 10(-8) ), and 6.2 (MH, p = 0.018). For all three PCR-vitro models, log(UF) correlates negatively with molecular weight (r(2) = 0.31 to 0.84, p = 0.017 to < 10(-6) ) but not with log(vapor pressure) as an additional predictor (p > 0.05), so vapor pressure appears not to explain the significant in vivo/PCR-vitro discrepancy. Until this discrepancy is explained, careful in vivo measures of Kup should be obtained for more chemicals, the expanded in vivo database should be compared to in vitro-based predictions, and in vivo data should be considered in assessing aqueous dermal exposure and its uncertainty.

Dermal Versus Total Uptake of Benzene from Mineral Spirits Solvent During Parts Washing

“…(39) However, the in vivo value of K p,eff for MSS measured in this study is substantially (∼30fold) greater than a K p estimate for benzene from recycled Safety-Kleen 105 (0.00013 cm/h) based on an in vitro study using occluded excised human skin. (23) This difference between in vivo and in vitro estimates is consistent with the recent comparison of aqueous chemical uptake by Bogen (38) and the comparisons of neat versus in vivo chemical uptake summarized in Table II. A major source of uncertainty/variability in this assessment is associated with the assumption of enhanced dermal uptake through damaged skin, concerning which somewhat contradictory evidence exists among relevant published studies. (57,58,(64)(65)(66)(67)(68)(69) Estimates of rates at which parts washers continue daily dermal contacts with MSS involving areas of severely damaged skin on their unprotected hands throughout their parts washing careers are not available and merit future study.…”

“…A recent comparison of in vivo studies of dermal uptake of dilute aqueous organic solvents indicated that K p,eff estimates obtained using guinea pig data were consistent with estimates obtained using data from human studies. (38) Recognizing that some uncertainty remains as to species differences in uptake in in vivo studies, the Dutkiewicz and Tyras (40) K p,eff estimate does not differ significantly (p = 0.52, by t-test) from that of K p,eff = 0.0082 cm/h implied by data reported by Morgan et al (81) for apparent permeability of neat benzene into clipped skin on the backs of 10 rats exposed for 24 hours. Interestingly, the effective permeability of three different formulations of liquid white spirits into tail skin of rats exposed for three hours (0.0075-0.0093 cm/h), calculated from data reported by Verkkala et al, (63) assuming a density for white spirits equal to that of MSS, also fall within the range of K p,eff values for neat benzene exposures.…”

“…Measures of steady-state dermal permeability (K p = J/C) obtained from in vitro diffusion-cell studies have been found generally to be lower than corresponding estimates of apparent "effective" permeability (K p,eff ) obtained from in vivo studies of short-term aqueous dermal exposure to dilute organic chemicals, even after increasing K p values to account for expected levels of nonsteady-state tissue loading. (37,38) This appears also to be true to an even greater extent for organic liquid exposures, as shown by limited available data summarized in Table II. Therefore, pertinent in vivo human data are preferred as a basis for estimating J BZ .…”

“…However, the in vivo value of K p,eff for MSS measured in this study is substantially (∼30‐fold) greater than a K p estimate for benzene from recycled Safety‐Kleen 105 (0.00013 cm/h) based on an in vitro study using occluded excised human skin . This difference between in vivo and in vitro estimates is consistent with the recent comparison of aqueous chemical uptake by Bogen and the comparisons of neat versus in vivo chemical uptake summarized in Table .…”

Dermal exposure from transfer of lubricants and fuels by consumers

“…There is evidence that in vitro measures of non-steady-state dermal uptake of aqueous and neat-liquid organic chemicals into skin can systematically and substantially underestimate corresponding dermal uptake that is measured using in vivo methods. 18 The Low 12 12 103 12 12 104 12 12 101 13 12 94 13 13 103 11 11 99 10 11 107 12 13 112 12 11 93 Medium 111 111 100 92 95 103 81 73 90 116 117 101 90 76 84 96 89 92 114 112 98 77 80 104 107 98 92 High 246 215 87 214 224 105 215 216 100 262 219 84 227 233 103 204 206 101 255 213 84 285 300 105 211 206 98 Recovery of diesel using m/z 216.20. Recovery of engine oil and bike oil using m/z 106.10. exposure scenarios were all carried out over a relatively short period of time, 6-8 min per test and a period of no more than 10 min between completion of a given exposure scenario and wiping the hands and forearms.…”