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0, laser processing of n Teflon (Polytetraorado. 77-82. CO, laser. SPlE801. we. HMSO,London. NDELSTADH, P. (i992) I v ~ 3. 6, 183-188. a 2 laser processing of Polymer Preprints 26. during processing of Ann. orcup. Hjq.. Vol. 31. No. 6. pp. 61MBS. 1993 Printed in Great Bntain. 00034818 93 %.00+0.00 Pergamon Press Ltd :1 1993 British Occupational Hygiene Society. RELEVANCE OF OCCUPATIONAL SKIN EXPOSURE VERA FISEROVA-BERGEROVA Department of Anesthesiology, University of Miami School of Medicine, Miami, FL 33101, U.S.A. (Rereired 2 March 1993 and in j n a l form 7 July 1993) Abstract-Dermal exposure gains in significance by the same token as permissible occupational inhalation exposures are lowered. The contribution of dermal absorption to the total dose absorbed during occupational exposure is apparent when dermal and pulmonary uptake rates are compared. Development ofan experimental data base for evaluation and control oldermal exposure is'hindered by: lack of suitable methods for measurement of dermal absorption in humans; interspecies differencesin skin permeability; regional differences in absorption rates due to non-homogeneity of skin composition and perfusion rates over the body; possible skin damage induced by the chemical or dispersant; and exposure conditions in the workplace. In the absence of sufficient human data, theoretical models can provide satisfactory information on dermal absorption. It is advocated that the current practice of using acute dermal toxicity ( L D ~a~s a) criterion for warning on the potential of significant dermal absorption be replaced by a criterion based on comparison of the dermal penetration rate with the pulmonary uptake rate at inhalation exposures permissible in the workplace. NOMENCLATURE selected increase in arterial blood concentration alveolar concentration arterial blood concentration concentration in skin inspired concentration mixed venous blood concentration concentration in saturated aqueous solution at 20C concentration in regional (subcutaneous)venous blood concentration gradient across the stratum corneum surface area of exposed skin perfusion rate tlux, penetration rate through the stratum corneum critical flux of the chemical in the liquid state (i.e. dermal uptake becomessignificantcompared to the inhaled amount) critical tlux d t h e chemical in the gas state (i.e.dermal uptake becomes significant compared to the inhaled amount) permeability coefficient median lethal dose bloodigas partition coefficient bloodiskin distribution coefficient wateridispersant distribution coefficient maximum concentrations permissible at the Workplace approved by Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (Germany) number of measurements octanol-water distribution coefficient cardiac output correlation coefficient reference value for acceptable workplace dermal exposure exposure duration threshold limit value for occupational inhalation exposure approved by the American Conference of Governmental Industrial Hygienists time-weighted average concentration alveolar ventilation 673 614 V. FISEROVA-BERGEROVA INTRODUCTION ~NDUSTRIALchemicals in the workplace can lead to exposure by inhalation, through the skin and gastrointestinally. Although gastrointestinal exposure can be avoided by good hygiene it cannot be excluded when inhaled particles are removed by the ciliary process. Inhalation exposure has traditionally been considered as the main threat to workers' health. For half a century, the main concerns of industrial hygienists were the control of airborne concentrations and the setting of occupational exposure limits for airborne contaminants. The health hazard from dermal exposure was recognized for only a few compounds (pesticides, phenols, amines) known to induce acute systemic toxicity upon contact with the skin: these carry a skin notation in listings of exposure limits [e.g. American Threshold Limit Values, TLV (ACGIH, 1992), or German Maximale Arbeitsplatzkonzentrationen,MAK (COMMISSION FOR THE INVESTIGATION OF HEALTH HAZARDS OF CHEMICAL COMFWUNDINSTHE WORK AREA, 199l)l. Dermal exposure is becoming more important as permissible occupational inhalation exposures are lowered. The significance of dermal absorption becomes evident when pulmonary and dermal absorption rates are compared. For example, it was estimated that, upon skin contact, liquid benzene penetrates the skin at a rate between 0.2 and 0.7 mg cm-* h (HANKE et al., 1961; MAIBACH and ANJO, 1981;FISEROVA-BERGEReOt aVl.A, 1990).The first TLV-TWA published in 1946 for benzene was 100 ppm (ACGIH, 1984). As the pulmonary uptake rate at this exposure (about 200 mg h- ') is significantly higher than the dermal penetration rate, the expected dermal contribution to total absorbed amount is negligible. However, since 1946 the inhalation exposures permissible in the workplace have been reduced by a factor of 100 or more, thus making pulmonary and dermal uptake equally important. Dermal absorption-and thus dermal toxicity-is affected by three factors: (i) physicochemical properties of the chemical (mainly solubility and chemical structure); (ii) differences in the nature of the skin (which varies from one part of the body to another, and differs between species); and (iii) differences in occupational exposure (dependingon the production and skill of the worker). Factors (i) and (ii) involve the mechanism of dermal absorption. MECHANISM OF DERMAL ABSORPTION The skin is made up of various types of cells which form three distinct layers: ( 1 ) the epidermis (in which the stratum corneum functions as a diffusion barrier), which is formed by layers of dead and living cells of thicknesses of about 10 and 40 pm, respectively; (2) the dermis, which consists mainly of proteins and blood cells (about 1250 pm thick) and which is perfused by about 3.3% of cardiac output; and (3) the hypodermis, consisting mainly of connective tissues and fat (about 1000-6600 pm thick), is perfused by about 2.2% of cardiac output (ICRP, 1984). Percutaneous absorption involves diffusion of the chemical through these layers until it reaches capillaries in the epidermis and hypodermis, and enters the systemic I circulatiol enzyme SI Derm; the stratu Penetr path ways. water and permea bi I penetratio by the eql where AC vary over corneum, perspira t i c MAIBACH. PIOTROWS chemical k thus flux- K and COncentra I measureml differences For examr was 0.006 I indicates a (DUTKIEW (TSURUTA, TYRAS, 19t (DUTKIEW TYRAS (19 ethylbenze Several on the phj properties structure a (EPA, 199: physicocht penetratioi Document 1986). Altt changes di [Equation becomes nc A 'repr average t hi tion, through the I be avoided by led by the ciliary e main threat to gienists were the posure limits for IS recognized for :acute systemic lngs of exposure 32), or German E INVESTIGATION , 1991)]. Dermal onal inhalation pulmonary and 1 that, upon skin 7 mgcm-'h-' 'tal., 1990).The , I , 1984). As the ntly higher than total absorbed rmissible in the pulmonary and :e factors: y and chemical rt of the body to tion and skill of :t layers: ( 1 ) the rrier), which is 0 and 40 pm, lod cells (about ,ut; and (3) the 100&6600 p n gh these layers rs the systemic Relevance of occupational skin exposure 675 circulation. The diffusion is governed by Fick's law. The epidermis also has a limited enzyme system and thus can metabolize xenobiotics (KAO et al., 1985). Dermal absorption involves two major diffusion processes, penetration through the stratum corneum and transfer into the capillary blood. Penetration through the stratum corneum, by diffusion via polar and lipophilic pathways, is restricted to small molecules (molecular weight < 500). High solubility in water and in fat facilitates rapid penetration. The measure of penetration is either the permeability coefficient (which is the velocity constant in cm h-') or flux (which is the penetration ratein mgcm-'h-'). Flux (F1)andpermeabilitycoefficient( w a r e related by the equation: FI =K AC, (1 1 where AC is the concentration gradient across the stratum corneum. Both K and F1 vary over the body, depending on the composition and thickness of the stratum corneum, the presence of skin appendages (hairs, glands) and the amount of perspiration. The differences among animal species are even larger (WESTER and MAIBACH, 1977). Environmental temperature and humidity (DUTKIEWICZ and PIOTROWSK1I,961) and, most importantly, the dispersant (vehicle) in which the chemical is administered also affect penetration. Moreover, the nature of the skin-and thus flux+an be gradually altered by the applied chemical or by the dispersant. K and FI can be measured both in vivo and in vitro. The determination of the concentration on the receptor side of the skin is the most controversial step in the measurement. The methods were recently reviewed by EPA (1992). Because of differences in skin composition and in methodology the results reported vary widely. For example, the flux of xylene, measured in a diffusion chamber using excised rat skin, was0.006mg h-' (TSURUTA, 1982),whereas excretion of metabolites in humans indicates a flux of 0.13 mg h - ' (ENGSTROeMt al., 1977) and 7.0 mg cm-' h-' (DUTKIEWICZ and TYRAS, 1968). Similar variability was reported for styrene: 0.03 (TSURUTA, 1982), 0.06 (BERODeEt al., 1985) and 12 mg cm-* h - ' (DUTKIEWICZ and TYRAS, 1968);and for ethylbenzene: 0.06 (TSURUTA, 1982),0.16 and 28 mg cm-* h-' (DUTKIEWICZ and TYRAS, 1967).The difference in values reported by DUTKIEWCaZnd TYRAS(1967) for ethylbenzene is due to differences in the application (liquid ethylbenzene vs solutions). Several theoretical approaches for the prediction of dermal penetration rate based on the physiological function of the skin and on the chemical structure and physical properties of the chemical were developed. Models based on similarity of chemical structure are reviewed in the EPA Interim Report on Dermal Exposure Assessment (EPA, 1992, pp. 5.21-5.32).Other modelsare based on thediffusion process and on the physicochemical properties of the chemical and skin composition. In these models penetration is defined either by permeability coefficients [reviewed in the same EPA Document (EPA, 1992, pp. 5.33-5.64)] or by flux (models reviewed by OSBORNE, 1986). Although the permeability constant is time-independent, the penetration rate changes during the exposure as does the concentration gradient across the skin [Equation (l)]. In uico, the change is apparent at the beginning of the exposure, but becomes negligible when the apparent steady state is approached. A 'representative' flux is calculated for a skin with average characteristics (Le. average thickness of stratum corneum and average diffusion coefficient), taking into 616 V. FISEKOVA-BEHGEHOVA consideration the aqueous solubility, the octanol-water distribution coefficient, and the molecular weight of the chemical compound involved (BERNER and COOPER, 1987). A simple equation for the prediction of flux of non-polar compounds from saturated aqueous solutions was derived by BERNER and COOPER (1987): F1=%15 (0.038+0.153 P) (2) ', '.where F1 is flux in mg cm-2 h- cSaiIs saturated aqueous solution in mg ml- Pis the octanol-water distribution coefficient, MW is molecular weight, and e is the base of natural logarithm. Numerical constants are derived from `representative' parameters which are pertinent to the diffusion process through polar and lipophilic channels of the stratum corneum. Predictions based on physical properties and chemical structure usually provide values which are in the range of experimental data. Thus, fluxes calculated for xylene (0.50 mg cm-' h-'), styrene (0.52 mg h-') and ethylbenzene (0.53 mg h-') (FISEROVA-BERGEROVA et al., 1990) fall within the range of the measured values cited above. Other examples comparing calculated and measured data were reported by FISEROVA-BERGEROVA and PIERCE (1989) and by OSBORN(1E986). The swellingof psoriatic skin immersed in a liquid chemical or its solution provides a rapid method for grading the penetration rate through the human skin (HANSEN, 1982). The transfer of the chemicalfrom the dermis into the capillary blood depends on the perfusion rate of the dermis (and thus on physical activity of the worker and environmental temperature) and on the dermis-blood distribution coefficient of the chemical (and thus on body fat and on the hydration of the skin) (FISEROVA- BERGEROVA, 1990).At the beginning ofexposure, when the absorption rate is a function of time, the concentration builds up in the epidermis and dermis. During this period, the concentration gradient diminishes. The absorption rate becomes constant after the lag time period, when steady state is approached (that is, when the penetration and uptake rates are equal and the concentration gradients are constant). The rate-limiting step is usually the penetration rate through the stratum corneum, but for lipophilic chemicals in poorly perfused areas it may be the removal of the chemical from the skin by capillary blood. Pharmacokinetic models were developed to describe the distribution and elimination of percutaneously absorbed chemicals (FISEROVA- BERGEROVA, 1990; GUY et ai., 1985). The passing of the chemical into the capillary blood at steady state can be described by a balance equation: INFLOW =OUTFLOW Fcar,+F1 = Fcven, (3) where F is the perfusion rate of skin under the exposed area and cartand e,,, are concentrations of the chemical in arterial blood and venous blood under the exposed area, respectively. If the diffusion is rapid, as in the case of volatile organic solvents, the concentrations in blood, alveolar air and dermis are instantly equilibrated and Equation (3) can be rewritten in order to compare the penetration rate with uptake rate: F1= (Cderrnibl/derm -Calvj.bl/air 3 (4) where cdcr and in alvc Derma The role c Dermal a pulmonar balance ec where V,, concentra define the If C m i x < ( Pulmona for chlori furfural (1 1980), st! pulmonai A Ph! short-ten organic confirmel increases ambient The workplac -for --dU --ex -prt -W< Form of In ar from ski and vap pulmon; I coefficient, and 1 COOPER, 1987). s from saturated g mi-'. Pis the e is the base of t we' parameters hilic channels of usually provide dated for xylene i0.53 mg cm-* .easured values 4 were reported ution provides skin (HANSEN, lepends on the s worker and efficient of the n) (FISEROVAte is a function ng this period, J nstant after the Tenetration and .e rate-limiting for lipophilic 1 from the skin describe the Is (FISEROVA) the capillary (3) and even are er the exposed lcsolvents, the iilibrated and e with uptake (4) Relevance of occupational skin exposure 611 where cdermand calvare concentrations of the chemical in skin under the exposed area and in alveolar air, respectively, and the 1.s are the appropriate partition coefficients. Dermal absorption is affected by other routes ofentry of the chemical into the body. The role of the lungs in the exposure to volatile chemicals deserves special attention. Dermal absorption increases the concentration in venous blood. Consequently, pulmonary uptake is reduced or is replaced by elimination, as evident in the following balance equation across the lung: INFLOW =OUTFLOW + ++`alv `ins Q +`mix = `atv Calv Q Cart- inspired venous return exhaled systemic circulation (5) where ValVdenotes alveolar ventilation, Q is cardiac output, and tins, cartand cmixare concentrations in inspired air and arterial and mixed venous blood, respectively. To define the pulmonary uptake or wash-out, Equation ( 5 ) is rearranged: -'atv(Cins -c a l v ) =Q(Cart Cmix). (6) If cmixe cart,pulmonary uptake occurs. If cmiX>car,,pulmonary wash-out occurs. Pulmonary wash-out of dermally absorbed solvents was documented experimentally for chlorine-containing solvents (STEWART and DODD1, 964; FUKABOeRt aIl., 1977), furfural (FLEK and SEDIVEC, 1978), methanol (SEDIVEeCt al., 1981;DUTKIEWCeZt a!., 1980), styrene (BERODEet al., 1985) and xylene (ENGSTROM et a f . , 1977). Extensive pulmonary clearance of volatile chemicals reduces their potential for dermal toxicity. A physiologically based simulation model was used to demonstrate the effects of short-term exposure of the hands on the concentration of hydrophobic and hydrophilic organic solvents in exhaled air (FISEROVA-BERGEROVA, 1990). The simulation confirmed that short, intermittent contact of the hands with liquid solvent significantly increases alveolar concentrations of solvents, possibly above the concentration in the ambient air, and thus pulmonary uptake is replaced by pulmonary wash-out. VARIABLES IN OCCUPATIONAL EXPOSURE The variables which are critical in the evaluation of dermal absorption in the workplace are: -form of the chemical; d u r a t i o n of dermal exposure; -exposed area (size as well as location on the body); -presence of other chemicals (mixture constituent, dispersant); and -workload and environmental factors (humidity and temperature). Form of chemical In an industrial setting dermal absorption can result from exposure to vapours or from skin contact with liquid chemicals or their solutions. Dermal absorption of gases and vapours of volatile chemicals (SVP>5 torrs) is usually negligible compared to pulmonary absorption (RIIHIMAKI and PFAFFLI, 1978; FISEROVA-BERGEROVA et al., 678 V. FISEKOVA-BERGEHOVA 1990). However, the vapours of chemicals with low vapour pressure, such as furfural (FLEK and SEDIYEC, 1978),or chemicals with high aqueous solubility, such as methanol (SEDIVEC et ai., 1981), can condense on the body surface, and consequently their availability for dermal penetration can be increased. Dermal penetration of solids (dust, aerosols, etc.) can be facilitated by their dissolution in perspiration. The duration of exposure Unless special protective apparel is used, the duration of dermal exposure to gases and vapours can be assumed to be equal to the duration of the chemical's presence in the air of the workplace. The duration of dermal contact with liquids and solutions depends on work procedures and on the skill and fastidiousness of the worker. The evaporation of volatile chemicals makes the estimation of exposure duration difficult. Another complication arising from the duration of dermal exposure is the change in the biDchemica1 parameters of the skin induced either by the chemical itself or by the dispersant. The biochemical change, which can develop rapidly during the lag period or slowly on repeated contact, usually alters the skin permeability. Exposed area of skin While the surface area of skin exposed to vapours and gases is the same as the whole-body surface, the surface area of skin exposed to aerosols, dusts and liquids is difficultto estimate. Protective apparel can reduce the exposed area, but contaminated, dirty apparel can enhance the chemical availability for dermal absorption (TROJANOWSKA, 1959). The surface exposed to liquids is usually only a small fraction of the total body surface. For example, the surface of the hands accounts for about 5% of body surface, and the surface of an outstretched palm and fingers accounts for about 1YOof body surface (ICRP, 1984).Spillscan result in an unpredictable dermal exposure of a large body surface. Moreover, the thickness of the layers of skin cells on different parts of the body varies so that the penetration rate varies (SCHEUPLEIN and BRONAUGH1,983). Presence of other chemicals Studies with drugs have proved that absorption and therapeutic effects depend on the vehicle by which the drug is administered (COOPER, 1985). The same applies to industrial chemicals. Dermal contact with a mixture of chemicals can alter the penetration rate by two mechanisms: ( 1 ) if the chemical is readily soluble in the dispersant, then the large distribution coefficient between the dispersant and dermis slows the penetration. Thus, the dermal penetration rate of dissolved chemicals appears to be directly related to their concentrations and inversely related to their solubility in the dispersant; and (2) prolonged contact with liquids usually results in biochemical changes in skin and skin permeability. If the dispersant damages the skin, then the penetration rate of mixture components is expected to increase. The relation between duration of the exposure (T),exposed area (EA),solubility in the dispersant (defined by distribution coefficient of the chemical between water and dispersant &,,d) and the amount absorbed is given in Equation (7): Penetrated amount =F1 . T . EA . &., (7) Workload and Since the hypodermis UI ambient temp absorption (I: In a recent review on der RIS Developn has been hint --lack of dermal -lack of -+aria b Methods Jor Evaluati absorbed (u surface (whi the chemic. recommend dermal exp 1992; COM COMFWUND evaluation presence of (FENSKE et apparel (F indicators against arc 1992). The does not r Database The in skin comr in applic. applicatic Derm example. listed in ! Data on 1 toxicity r (Fig. 1). . that the ( .such as furfural such as methanol nsequently their tration of solids .ation. xposure to gases -ai's presence in s and solutions the worker. The uration difficult. e is the change in 11 itself or by the ie the lag period le same as the and liquids is contaminated, .ption (TROJAfraction of the r about 5% of unts for about m a l exposure 11son different HEUPLEIN and cts depend on me applies to can alter the .e distribution ius, the dermal Jted to their t; and ianges in skin .ration rate of 1, solubility in :en water and (7) Relevance of occupational skin exposure 679 Workload and environmental factors Since the dermal absorption depends on blood perfusion of the dermis and hypodermis under the exposed area the absorption rate increases with movement and ambient temperature; this means that increased workload and heat enhance dermal absorption (DUTKIEWICZ and ROTROWSIK96I1,; FISEROVA-BERGEROVA, 1990). In a recently published monograph, GRANDJEAN (1990)provides a comprehensive review on dermal absorption with respect to workplace exposure. RISK ASSESSMENT OF OCCUPATIONAL DERMAL EXPOSURE Development of the criteria for risk assessment of dermal exposure in the workplace has been hindered by three major problems: -lack of quantitative methods for direct measurement of dermal exposure and dermal absorption; -lack of data on chronic dermal toxicity; -variablesin dermal exposure in an industrial setting. Methods for measurement of dermal exposure Evaluation of dermal exposure can be based either on the amount percutaneously absorbed (which is related to the health effect) or on the contamination of the skin surface (which is related to the availability of the chemical). Biological monitoring of the chemical, which is a measure of the amount absorbed (internal dose), is recommended for assessment of occupational exposure to chemicals with potential dermal exposure, and appropriate reference values are being developed ( A C G I H , 1992; COMMISSION FOR THE INVESTIGATION OF HEALTH HAZARDS OF CHEMICAL COMPOUNDS IN THE WORK AREA, 1991). Three basic techniques are used for the evaluation of skin surface contamination: wiping techniques are used to assess the presence of chemicals on the surface of workshop facilities and on the skin of workers (FENSKE et al., 1987);fluorescent tracers are used to evaluate the efficacy of protective apparel (FENSKE et al., 1987; FENSKE, 1988); and pad techniques using colorimetric indicators are being developed to warn instantly the worker that the skin protection against aromatic amines, isocyanates and organic solvents is inadequate (KLINGER, 1992).The contamination measurement may not reflect the health risk if the chemical does not readily penetrate the skin. Database on dermal toxicity The information on dermal toxicity is biased because of the diversity in interspecies skin composition, function and appendages (hairs, sweat),and because of the diversity in application of the tested material (immersion and open or covered topical application with or without the dispersant). Dermal toxicity is usually tested in rabbits, but the existing data are sparse. F o r example, L D ~ ,for acute dermal toxicity is given for only about 1% of the chemicals listed in the N I O S H REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES (1979). Data on chronic toxicity are even more sparse. The shortage of data on acute dermal toxicity may be circumvented by considering the similarity of oral and dermal L D ~ ~ (Fig. 1).The regression shows that the dermal LD,, is about double the oral L D ~ ,and that the correlation between them ( r=0.884, N = 5 0 ) improves when data obtained in 680 4 4.51 f V. FISEHOVA-BEKGEKOVA 0 '1 0.5 0.5 1.5 m Rabbit *Rat oDiffcrent species I 2.5 LOO ORAL(mg/kg) 3.1 5 41.5 FIG. I . Comparison of LU~,, for acute oral and dermal toxicity. LD~,,for dermal and oral administration (mg kg-') of 50 randomly selected chemicals from the NIOSH Registry of Toxic Effects of Chemical Substances are plotted in log-log scale. Each point represents the pair of data obtained in the same animal species ( W rabbit, 0 rat) or in different species (0)T. he regression for all 50 chemicals, shown as a line, is: log dermal =0.780 log oral +0.873 (r =0.84).The regression for I5 points obtained in the same species (not shown in the figure),closelyfollowsthe line for 50points: log dermal =0.763 log oral +0.929 (r =0.910). Both coefficients indicate a significant correlation (P<O.Ol). the same animal species are compared ( I =0.910, N = 15). Differences between animal species are greater than the effect of the route of administration. CRITERIA FOR ASSESSMENT O F OCCUPATIONAL DERMAL EXPOSURE Acute dermal toxicity In the absence of data on chronic dermal toxicity, policy making organizations such as the American Conference of Governmental Industrial Hygienists (ACGIH) and Deutsche Forschungsgemeinschaft (DFG) base their criteria for skin notation mainly on acute dermal toxicity (usually dermal LD,, in rabbits or rats). Several articles criticise inconsistencies in skin notation (GRANDJEAN et al., 1988; SCANSETTeIt al., 1988; FISEROVA-BERGEROVA et al., 1990; HANSEN1,982). All critics concluded that the list of chemicals with skin notations is incomplete and sh.ou. ld include additional chemicals which can be significantly absorbed through the skin. According to the latest guidance from the TLV Committee of ACGIH, the chemical should carry a skin notation if its dermal L D , ~is smaller than 1 g kg-*, or if the likelihood of dermal absorption is otherwise indicated,for example, by solubility of the chemical or by its chemical structure (ACGIH, 1992). To test the L D cr~ite~rion, 50 chemicals randomly selected from the NIOSH Registry of Toxic Effects of Chemical Substances w smaller than the chemical! notation. Th figure shows during an 8- 2.: Y! ?c 1. Crr -5 Carr Iy a0 8 0 w 2 4 I -O t 0 0, -1 FIG. 2. Dern dose inhaled (mg m-') by chemicals art for skin nota TLV-BE1 B( Pulmonar Basin; the reguli the chror organs fc acute tox toxicity i To o\ penet rati concent r 1989). T' 1 4.5 oral administration Cffects of Chemical ! in the same animal .shown as a line, is: ne same species(not ) 2 9 ( r = 0 . 9 1 0 ) . Both s between animal XPOSURE .anizationssuch , (ACGIH) and notation mainly Several articles -'ANSETTI et ai., cluded that the .ude additional H, the chemical kg-', or if the jolubility of the jo criterion, 50 :ts of Chemical 2.5 e? 1.5 9, 8 682 V . FISEHOVA-BEHGEHOVA calculate a 'critical flux', that is, a flux which would increase the biological level by a chosen amount above that reached during the permissible inhalation exposure: INFLOW = OUTFLOW where the symbols are the same as in Equation ( 5 ) , with the exception of the concentration of the chemical in mixed venous blood (cmixw),hich reflects the average concentration in venous blood from all tissues, excluding the amount absorbed from the skin under the exposed area, EA. F1 is flux. If dermal exposure does not take place, F1. EA = O and Equation ( 5 ) applies; but if dermal absorption takes place, the concentration of the chemical in alveolar air, blood and tissues increases. A flux for the permissible increment of biological levels, F1*, can be calculated when these two situations are compared and EA is defined. For example, contact with liquid will increase biological levels by 30% if FI,,, is defined by Equation (9): After substituting from Equation (6)and defining EA (EA =360 cm', stretched palms and fingers)and Val"( V,,, =90 1. h- I ) a simpleformula for the calculation of critical flux (expressed in mg cm-' h - I ) is obtained: F1*li, =3/4 TLV. (10) A similar calculation can be made for whole-body exposure to a vapour (EA= 18 000 cm') where c,,( is saturated aqueous solution of the vapour and A is its water-gas partition coefficient (FISEROVA-BERGEROVA el a]., 1990). The Biological Exposure Indices Committee of A C G I H denotes chemicals with measured or predicted flux larger than the critical flux, in order to draw attention to the possibility that biological levels may not be a quantitative indicato'r of inhalation exposure. A similar algorithm was suggested for the evaluation of the potential for dermal toxicity and the development of a criterion for skin notation. Tripling biological levels by exposure of hands to Liquid is considered as critical, and recognition of the potential for dermal toxicity is suggested for all chemicals with a flux value (in mg cm-' h - ' ) greater than 5 x TLV value (in mg m-') (FISEROVA-BERGEROVA er al., 1990).From 122 chemicals for which flux was predicted (FISEROVA-BERGEROVA et al., 1990),a significant dermal toxicity potential upon contact with liquid is indicated for 77 chemicals (63%); of those, only 40 (52%) carried a skin notation in the 1987-1988 TLV-BE1 Booklet, and only 41 (53%)carry a skin notation in the 1992-1993 booklet (skin notation was added to methyl n-butyl ketone and methyl chloride and removed from p-phenylene diamine) (ACGIH, 1987, 1992). In the workplace, the threshold for flux can vary depending on the exposed area, the duration of dt estimate a re conditions, th The formula where AB1% the level reac body surface and TLV is t 1 a dermal ove 1990). The am1 significant : workplace. and suffers suitable foi exposure 11 theoretical absorption (which rela LD,, (whic acute and ACGIH (19 (Edited t Hygienis ACGIH (19 of Gove ACGIH (19' of Gove BERNER,BI by K Y D BERODE,M absorpt COMMISSIO" (1991)\ Report COOPER,E ogical level by a i exposure: (8) xception of the lects the average ' absorbed from -1 J applies; but if ,eolarair, blood 1 levels, F1*, can ,d.For example, led by Equation .retched palms 1 ofcritical flux '--gas partition hemicals with ttention to the of inhalation ial for dermal Jiologicallevels f the potential ig cm-' h-l 1 30).From 122 1, a significant micals (63%); -BE1 Booklet, 1 notation was .I p-phenylene osed area, the Relevance of occupational skin exposure 683 duration of dermal exposure, and the selected threshold for the biological level. To estimate a reference value (RV) for dermal exposure existing in the workplace conditions, the following formula can be derived from Equation (8): The formula can be simplified to: R V =0.4 AB1% * TLV EA% * h ' where AB1% denotes the chosen increased biological level expressed as a percentage of the level reached during exposure to TLV-TWA only, EA% denotes the percentage of body surface dermally exposed, h denotes the duration of dermal exposure in hours, '.and TLV is the TLV-TWA in mg 1- If flux exceeds the referencevalue (F1>RV), then a dermal overexposure at the selected B1-level is predicted (FISEROVA-BERGEROVA et al., 1990). CONCLUSION The amount of chemicals percutaneously absorbed in the workplace can be as significznt as the amount inhaled during the current permissible exposures in the workplace. The database for quantitative evaluation of dermal exposure is scattered and suffers from a lack of data on chronic dermal toxicity, from a lack of methods suitable for routine evaluation of dermal penetration, from variability of dermal exposure in the workplace, and from variability of skin composition. At present, theoretical models fill the gap resulting from lack of experimental data on dermal absorption. Criteria based on comparison of pulmonary and dermal uptake rates (which relate to chronic toxicity) should be preferred to criteria based on acute dermal LD,, (which are burdened by interspecies differencesin skin composition, differences in acute and chronic toxic endpoint, and effect of mode of application and dispersant). REFERENCES ACGIH (1984) Threshold Limit Values-Discussion and Thirty-five Year Index with Recommendations (Edited by M. E. LANIERV),ol. 9. p. 343. Annals of the American Conference of Government Industrial Hygienists. Cincinnati, Ohio. ACGIH (1987)Threshold Limir Values and Biological Exposure Indicesfor 1?87-1988. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. ACGIH (1992).Threshold Limit Values and Biological Exposure Indicesfor 1992-1993. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. BERNER, B. and COOPER. E. R . (1987)Models of skin permeability. In Transdermal Delivery ofDrugs (Edited by KYWNIEUSA. . F. and BERNERB..), Vol. 11, pp. 41-55. CRC Press, Boca Raton, Florida. BKRODEM, ., DROZ, P. 0. and GLILLEMIMN,. (1985) Human exposure to styrene. VI. Percutaneous absorption in human volunteers. Int. Archs occup. Environ. Hlth 55, 331 -336. COMMISSION FOR THE INVESTIGATION OF HEALTH HAZARDS OF CHEMICAL COMPOUNDS IN THE WORK AREA (1991) Maximum concentrations at the workplace and biological tolerance values for working materials, Report No. XXVII, VCH Publishers, Weinheim, Germany. COOPER, E. R. (1985)Vehicle effects on skin penetration. 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