Document a49n7akr0zdpK90GggdGv5Lpa

American Journal of Epderridogy . Copyright o 1997 by The Johns Hopkins University school 0/ Hygiene and Public Healih AH rights reserved Analysis of Current Trends in United States Mesothelioma Incidence Vol 145. No 3 Panted in U.S.A (fat, rthe iO 37 Bertram Price Mesothelioma incidence often is interpreted as an index of past exposure to airborne asbestos. The mesothelioma rate for US males exhibits an increasing trend throughout the 1970s and early 1980s. The trend has been attributed to occupational exposure in the shipbuilding industry during World War 11, in manufac turing, and in building construction. Incidence data (1973-1992) from the Surveillance, Epidemiology, and End Results Program were used to investigate current trends in age-adjusted and age-specific mesothelioma rates. An age and birth-cohort model was used to project both lifetime probabilities ofmesothelioma by cohort and the annual number of cases expected over the next 70 years. The current trend in female rates is flat (age-adjusted rate = 0-30 per 100,000). The estimated lifetime risk for females is 2.5 x 10"', independent of birth cohort. The projected average annual number of female cases is 500. For mates, the age-adjusted mesothelioma rate is increasing solely due to the age group 7,5 years and over, albeit at a declining growth rate, fdetime risk for males peaks at 2 x 10-3 for the 1925-1929 birth cohort, then decreases to 5 x 10 -4 for the 1955-1959 birth cohort The pattern ofrates reflected in the age and birth-cohort model suggests a peak in the annual number of mesothefioma cases for males at 2,300 before the year 2000. The number oymale cases then will drop during the next 50-60 years toward 500. These trends mirror the US trend in raw asbestos consumption and a reduction in workplace airborne asbestos levels. Am J Epidersiol 1997; 145211-18, asbestos; incidence; mesothelioma Mesothelioma incidence often is interpreted as all index ofpast exposure to airborne asbestos. The inci dence of mesothelioma for United States males exhib its a generally increasing trend throughout the 1970s and early 1980s (1-3). The trend has been attributed to occupational exposure to asbestos, which, for some workers, was substantial from the 1930s through the 1960s (1, 4). Occupational exposure in the United States during this time period occurred in the ship building industry during World War It, in manufac turing, and during building construction (1,2). Cur rently, exposure potential exists for asbestos removal workers; workers conducting renovations in buildings with asbestos-containing material; and maintenance, repair, and custodial workers in buildings with asbestos-containing materials. These exposures, how ever, are orders of magnitude lower than historical occupational exposures (5). Trends in mesothelioma incidence rates have been studied using various databases and methods both in Received for publication May 13,1996, and m final form October 30,1996 ,, ... ' Abbreviations: SEER, Surveillance, Epidemiology, and End Re sults; SMSA, Standard Metropolitan Stansfical Area From Price Associates, Inc., Washington, dc. Reprint requests to Dr. Bedram race, Price Associates, Inc., isooK Street, N.W, Suite 718, Washington, dc 20006. the United States (3, 6-8) and in the United Kingdom (9)_ Spirtas et al. (3), using incidence data from New York State; Los Angeles County, California; and the Surveillance, Epidemiology, and End Results (SEER) Program demonstrated a statistically significant in crease for males over time by comparing data for 1977-1980 with data for 1973-1976. Peto et al. t9) analyzed death rates from mesothelioma registries in England, Wales, and Scotland. They reported an in creasing trend in the 1970s and 1980s and a continu ation of the trend for men now under age 50 years, most of whom began work in the mid-1960s or later. They concluded that exposure in the United Kingdom was greater around 1970 than in any previous period and that mesothelioma rates will continue to increase as that generation ages. Mesothetioma data from the SEER Program data base (10) for 1973-1992 were used to analyze current trends in age-adjusted and age-specific US nlesotheiioma rates and to project lifetime probabilities of con tracting mesothelioma for birth cohorts beginning with the 1885-1889 cohort and continuing through the 1955-1959 cohort. The results of the analysis show the downward direction ofmesothelioma incidence in the United States. The pattern of mesothelioma inci dence mirrors the US trend in raw asbestos consump tion, which approached peak levels during World War 212 Price II, as weII as the timing and impact of government regulations that address asbestos exposure. MATERIALS AND METHODS Mesothelioma (pleural plus peritoneal) incidence rates were developed from the SEER database, which represents 9.5 percent ofthe US population (11). The database is organized by case. Each case is identified by age, sex, race, date of diagnosis, and other infor mation characterizing the cancer type. Data on malig nant mesothelioma of the pleura and peritoneum were compiled by selecting cases with Intentational Clas sification of Diseases, Ninth Revision, morphology code 905 and topography code 163.9 for pleural me sothelioma and codes 158.8/158.9 for peritoneal me sothelioma. These data were used to develop rates for 5-year age groups in each diagnosis year. Three sets of rates were analyzed: 1) age-adjusted rates; 2) age- specific rates for 10-year age groups; and 3) 5-year age-specific rates for 5-year birth cohorts beginning with file 1885-1889 cohort and continuing through the 1955-1959 cohort. . Trends in age-adjusted and age-specific rates were investigated by fitting a three-parameter logistic growth curve (i2) to the data. The logistic curve smooths fluctuations in the observed incidence rates and highlights trends. The. logistic growth curve equa tion is: Y = 01/(1 + w X exp[ _ R3 X X]) where Y = age-adjusted or age-specific mesothelioma rate; X = diagnosis year and J3 = growth curve parameters. The distribution of male and female mesothelioma incidence Tates by age and birth cohort were analyzed by Poisson regression (13, 14) to obtain models that could be used to project future mesothelioma inci dence and lifetime mesothelioma risk. Mesothehoma counts extracted from the SEER database by age and year of diagnosis were translated into 5-year age group counts for each 5-year birth cohort. Person-years for each age and birth-cohort group were developed in a similar manner using population counts recorded in the SEER database. These data were used to fit - a standard age and birth-cohort model: u,t = a, x j. where lr *s the incidence rate for the ith age category and jth ftirth cohort; a, is the age-specific incidence rate for the ith age category; and cj is a measure of the cohort effect for the jth birth cohort. The model was fit by the maximum likelihood method using GAUSS (Aptech Systems, Inc., Maple Valley, Washington). The cohort effects (i.e., I c~ji were normalized by forcing c9, the effect for the 1925-1929 birth cohort, to take the value 1.0. The other cohort parameter values, therefore, may be in terpreted as estimates of relative risk (i.e., relative to the 1925-1929 cohort). For this parameterization of the age and birth-cohort model, (a,) represent agespecific mesothelioma incidence rates for the 1925 1929 birth cohort. Predicted mesothelioma counts were obtained for the ith age group andjlh birth cohort group by multiplying the incidence rate (uv -- o, X C) by the person-years for that group. DEVCAN (15), the National Cancer Institute life table analysis procedure for estimating lifetime cancer probabilities, was used to project the lifetime proba bility (also referred to as lifetime risk) of contracting mesothelioma for each birth cohort. DEVCAN re quires age-specific mesothelioma incidence rates, agespecific mesothelioma death rates, and agespecific death rates for all causes. For each cohort, the mesothelioma incidence rates used with DEVCAN were the observed rates calculated directly from SEER data, where available, or the predicted rates from the Poisson regression otherwise (i.e., ^ X d for the (ij)th age and birth-cohort group). Because mesothe lioma is considered to be fatal within I or 2 years after diagnosis, the mesothelioma death rate was set equal to the incidence rate. Male and female death rates for all causes were based on US mortality statistics for 1990. Approximate 95 percent confidence intervals foT lifetime risk were determined by Monte Carlo simu lation. Monte Carlo replicates of lifetime risk were developed by using the observed mesothelioma counts for each age and birth cohort group as expected values for the Poisson distribution. Based on these expected values, a new set of Poisson distributed mesothelioma counts were generated (16), the parameters of the age and birth-cohort model were estimated from these counts, and DEVCAN was applied to compute lifeti me risk for each cohort. This procedure was repli cated 100 times- A confidence interval was calculated for each cohort from the mean and standard deviation of the 100 replicates. The Poisson regression models and DEVCAN also were used to project the number of mesotheiomn cases for males and females in the future. Historical counts of male and female births were used as starting populations through the 1990-1994 birth cohort. Fu ture birth cohort populations were assumed to be the same size as the 1990-1994 cohort. To project beyond the 1955-1959 cohort, the downward male trend was continued by using the 1885-1889 birth cohort inci dence rates fr the 1960-1964 birth cohort and the average female rates for all subsequent cohorts. To project mesothelioma cases for females, the average Am J Epidemiol VoL 14Sr J\'c. 3, 199? vc i i of 31H1IS abort r ' life nicer ubacttrtg l rcageSfc* i. ihc TAN EeR t the r the >the-after f&i tt'miwerc duos -cted Crna /4$t hcse itetepli-.' .jj'wd' it ion also . run, !'tills: itetild;1 was liBSJigL cage- ? trends <n Mes*^^Oftia.:incKfertGe 213 femaic rate was applied to ail cohorts after trie 1955 1959 cohort. Other parameters required for the analy sis were the same as those used to project mesotheli oma risk: Mesothelioma death rates were set equal to incidence rates; and .mortality from all causes was based ox* US 1990 mortalijy data. RESULTS Trends Inago-udjustedriates Tfends in age-adjusted mesothelioma iticirfiinajj wete anatyicd for Jixaks and females by fitting a thcce-parameter logistic growth curve {figure l). The logistic grhwth curve does not provide a completely satisfactory fit for the female rate (p = 043)> which is small and virtually constant over the 1913-1992 inter val. An alternative model, with o constant mesotheli oma rat for 1973 through I9S2 and .a different eoti- staiil rate for 19S3 through 1992, provides a In:(ter fit to ihcdatu (/t 0.03). the rata estimated for 5973 1982 is 0.25 per 100.000; tiro rah: for 1983-1992 is- 0;3O.;per .HXMXXS,.. , ' Plots of (he observed Tlttedamtes .{figuro I) 'slimy: '%* rotmsi^eiidy rate; for males versus fqfnaksihcfpss aliycarsfh)' aj^Mtve:tirohdvei;siisycar: forxtkfe.; an3 "3) hlvtealjjvcdmtaaf.rhtb for: fewaies versus year. higure4:atea;in3icatt'a:d&l<fi7hg;annal growth rate for males and a -zero ^p.wth -fateriTOr- : females, Based i* thdTsfted ?uf?es;th'e:0owift rats lor imlcs-Tdl from 1.4.0 percent Tor 4973-4974 to 04 pefccht for 4 991-1992. Tiiejp-QWUi Site for females is zero, wich the exception of 1982-1033, when a or,climc increase in the level by 20 percent occurred. Trendsin ago-specific rates Trends in egc-spctjftc incidence rates for age groups45-^54,55-64, '65-74, and 75;years drmqrc'afc. shown'm figero 2 For age groups 55-64 and 65-74 years, the tread is flat after ,1933..For theagegroap 75 or more, incidence still is increasing in 1992, however, al a lower growxh rate than rh previous years. ft>r each age group, the growth rate is declining. With the exception of the. agc; ga^ip 45i-54 years,, which shows a decline In the rate -over, time, the growth curve was fit ( each set of data, {fitted curves not shown). Table 3 contains a summary and comparison of growth rates for 1982 and 1992 estimated from the fined em'es. Tho agegroup 75 years rmwe has the: highest growth rale in 1992. 3.0 percent, down from 7,7 percent itt 1932. Growth rates lit 1902 for the other ago groups are virtually seen), and for the age group 43-54 years, the growth rats, is negative. Predicted counts end fifotime probntaility iritk) of oiesqtheiitima ` ` . ' Predicted -and observed tireiothdioma counts for males on rite basis of Poisson raeref-sran analysis of rite - $BR data are shown in table 2.. The- relatively. small differences - between observed and predicted S f*;; ':-W$: ;Piifeft ssn:a "DfiEiig.-1, MalBLft^t^^ciSeirtest^ifc^tabiQldcnit?! tnfttuial ^jtwitjsnaalJ'jjro^.8j:Taio!i la 'SSijyiit i932tjased or. the tiiffie^atflrTieler lQjiiijc ijfiiwth curve \&2T laaais&j 45-54* 6*,-?kt 275 -2,2 as 3.2 7.7 -Z.fi 0.1 tu 3.0 - . * The s-S^sSi; growls curve was net Rt wifissd-dabi ifteduga the fric^bnta rata Seeling^f.wwktttjii growth ndies fes II* liWo ware SilivoS-iama ShalijtH Snot* (yj. 1 ,,413:- QffiEtS X,i,i* V2......., IO;Rf;^.0.1*t.-jB,vtiliW3i*OjS3),' ' ftha data <*shrvatsiii Rjir'-jaiSMrfrite traateS'as 3ft owfer ami V<as^;fis5d ihtsbtwrihc. tthjtsBc ft.fsa'a ^jutS 2j, mode}1 adequately-atpuiresAlic 'iT^^lh^SiMh^i^cfctrei^s, ............. ........... " ,jifc: table analysis: results are shown lii: pgjufeS^tfte'-two Gttjycs i: figure 3 drepSayllfelime inesoUielkma, risk' versus" birth 'cohort- foy ;tijalw:'and females. .fflie b^aMiSpproxttiiaie 95 tjjerasnft;:ci>nfr dence liwiK>i^jii(8ii'.r#a Monte Cafto' siitnijistion.) The curve fcf hilifes; increases,. iieadurtgi h;-Kt'iitirni:>m risk of appr^imsmly %:& iO:'J.foc;.ilio: 1925^13.2^: birth cohort, and d)d5'4t.riiaMS:,-Staiisikst3 rests(nol shown) cc^^ririg ifo riskier ilia 1925-1923 cohort with risks fdr:.: sijbscqoeh*. ajlibris substantiate the downward trendifct midst,-Th&risk curve for females. Jfe S5fctblly fiat,.#level approximate# 'equal-lo 2.5 \ 10"^. Praloctcd ndfhbf of me^iqithelioma cases prt^cckd ;namUe;rs .of mesothelioma cas|st':;are displayed m figure 4, GW die basis ol characteristics-of t^sscriiied above, the number, 'offdnalo dash's kiiliemaiti' c'dtjstahint^ppfoxlniatel'y 5Qfl per ycar . Thii number of mak;rot^ff>el)Ottia.eiises is likely to peak before the.year. 20O0;ai- approximate# 2,309 cases and then deeHhd io hppfbstmately 2>00 .eases' pts-yeatby 2Q55; '- DISCUSSION :-. Tilts analysis of mesotlielsqaia incidence trends- rejjptibd here is based pn data scoliected in rise SEER program, which may be'interpreted as a sample rep* resibtiBg tfielTS pppiiiaiidtt. The SEER I'nigram eov.ers five states: Connecticut, iowa, NeiyMexko, Utah, and Hawaii, and four metropolitan areas: Uctroil Stan ; derd Metropolitan Statistical Area fSMSA), Atlanta. SMSA, Sait FrantiscoOakluntl SMSA, and SantllcPuget Sound- These regions include 9,5 percent of the US population (11). Walker ci at, (37) suggested that 5EER data overestimate mosotlidioma incidence be cause of a dispttifiortioTWc number of shipbuilding areas in the SEER regions, Nicholson (1) argued that the SEER data underestimate mesothelioma incidence because large urban areas^ where asbestos.was used iniBariufactiiring;and"c<Kistnictioihare itmkrrepresefUed. Spinas et ak (3) compared the whim male pleura! cancer mortality rate for tile SEER regions with the At. J EpiUmiOl- Vot. 14S, to. 3,11397  fjf S 3- `-s > 3 :*. :$. tfiBLEit/Mli S1' f ... tCl : . . .oi iOteies^j: ,'S& C..OS6S --A 18^1864 tr* 0.2O2 a2 <*9ssys.: p 0.3S6 *0 . tiJ 190O-19W Stfli ' 9.591 :e;*k; 'KW^: 'S3i8f. 0.34S 0,76? lOitKOM". C.7S7 1515-1915 "fcm ID2IM934 O:B30 t#$-1S2& 1.000 1930-1534 0.769 ' 3427 1350-1054 5J3 104S-1946 0.40J 7890-1394 1988 ; 1955-5959 0.191 0 12 Q s. 0.1 S.0 <1 3- ! 4 .. 0.1 1.4 ' M- V V ... 0 i:o- . r.s 4.6. .V. 0 .. 5 Oil 1.5 is 0 0.3 S : 3.1 4 0.6 6 : 5.9 7 i;d O' 18 45-49 .<& 40-54 1.737 0 0.7 to :93. 7M' is:. 11.3 10 v 3,G & W 3 ';'4! i?- 2&t 22 27.5 3. ini: -2S, M4- '.4. 4.6; 3`,'.7 .22 . 04.6 S3 k&? 23 34.6 24 0 iJ^S S5-$9 M>S3 i 22 37 ' 47.9 67 71,2 Si 7.4.2 63 S2,a s 610 -&; B5- 4,6 7.641 " 75-70 11,634 . 1.5.175 3. S3 -43 54 ;1 91 3?;? 103 ms ,m. 90.1 17 19.1 7 M 43 07.4 im iSolsSf 120 140 ., 137.6 1 1;8 47 2@ toO 100.4 117 117.7 155 t38,1 ;.S0 39.6 27.0 1 0,5 SB 324 70 69.7 103! ti.7 116 tlfi.9 & 3S4 itt-Ml 0.S 13 12.6 37 337 SI :#s: 79 802 ;M. tsi 4.8 ZSrr. 20:.6 271' 32,63V 27.5 w 74 firiatOw7Bracrib8lceJlt,Cl7sWi^^ ^ g Sbsjjus ,w ftjf siob ijjt& cotibftftblrth soften panwiriw) xiago-sjMMifseiaf*) tripor-sw-y^'i;]. pnKwim nornbatin mosuttisfema* - . ,% 109105:too), S'% & 3 S fyi til: .. . i flGUREOi. trosoibslScirna Jpteuial +pcrttooEaJ>itr>q! 35% cwtfstfarce.Internals.DEVpA^W*-'ialia snobitSbas-k} Novciptoar. 1S9S,................ .; ^ y .- -... iotal US rate and concluded that the SEER data may overestimate the national incidence. hut that analyses of trends based on these data would not be affected. With respect to selected demographic and epidemtojlogsc factors, the SEER regions are reasonably repre sentative nf the US Tire trend in female rates is a baseline or back ground for evaluating mesothelioma incidence trends in general (2), The trend in age-adjusted incidence'for females is ussentisdly fiat, exhibiting a. constant rate of 0.25 per! 00,000 until J9S2 and then a slight'increase so OTQper lOO.QGP from I9S3 through 1992 (figure J). 'Die shift.Shat occurs in the 1982-1933 time inlers'uliS'nKJ.si liltely^a'diagriosstccffcct^ a coieietjiSKiieeof Enviromncntal Protection Agency regulatory activities during tire 1980s (l8-27). Ctmncny ct til. (8) conclude that Oie diagnostic effect in US; data is real; but note that any targe impact due to diagnostic changes is unlikely. Am aiicniatiye explanation of the small shift in tire fensate rale, namely that CnvireniKcnia! expo sure to airborne Asbestos is increasing, is not supported by tire data. 7he absence: at a steadily increasing age-adjusted rate for females makes ``increasing, envi ronmental asbestos exposure" unlikely as an explana tion for tire shift. The increasing trend in age-adjusted rates for males is due to the continuing upward trend in thcage group 75 years or more. Growth rates for the age group 15 or Am. J ttfiidcmio! Vo1.ms, No. 0, 139? Trends in Mesothelioma Incidence 217 more, although positive, are falling (table 1), Growth rates for all other age groups are near zero or are negative. These general trends in age-adjusted and agespecific rates (figures I and 2) are represented by the three-parameter logistic growth curve. The curve is a model for quantities with growth rates that decline linearly as the quantity increases (12). The logistic curve has been used in this analysis to smooth fluctu ations in incidence rates over the range of the observed data and thereby highlight trends. It cannot, however, capture downward trends in incidence. Therefore, it has not been used in this analysis to make quantitative projections of incidence beyond the range of observed data. The overall dynamics of long-term growth and de cline in male mesothelioma incidence are reflected in the pattern of lifetime risk (figure 3). The maximum lifetime risk appears for the 1925-1929 birth cohort.' Male members of this cohort would have been at work i n shipyards, manufacturing, and construction during the years 1930-1960, a period of increasing and max imum asbestos consumption in the United States. Sig nificant growth in the use of asbestos began in the 1930s, was halfway to peak consumption in 1940, peaked in 1950, where it remained until 1970, and then declined precipitously (2, 28). Workers bom after 1929 have experienced fewer years of exposure at peak asbestos consumption levels. Workers bom after 1929 also benefit from the Oc cupational Safety and Health Administration and the Environmental Protection Agency asbestos programs. The Occupational Safety and Health Administration has reduced its permissible exposure li mit four times since 1971 (29-31), and the Environmental Protection Agency restricted the use of asbestos in building con struction and imposed work practices for building demolitions (32)_ Currently, the potential for asbestos exposure, albeit at very low levels relative to historical worker exposures, remains only for asbestos removal workers; workers conducting renovations in buildings with asbestos-containing material; and workers con ducting maintenance, repair, or custodial activities in buildings with asbestos-containing material. The overall dynamics of long-term growth and de cline in mesothelioma incidence have been analyzed using the standard age and birth-cohort model. From a modeling perspective, the age and birth-cohort model provides a more detailed and accurate basis for pro jecting mesothelioma trends than do trends derived from age-adjusted and age-specific aggregates. Nev ertheless, the model is an approximation, and the amount of data available for the earliest and most recent cohorts is sparse. However, the relatively small differences between observed and predicted mesothe lioma counts (table 2) indicate that the model ade quately captures the general trend in mesothelioma risk. The estimates of lifetime risk reflect a relatively large degree of statistical uncertainty for the most recent birth cohorts (refer to the 95 percent confidence intervals in figure 3), but not large enough to obscure the-overall downward trend. The projected number of mesothelioma cases for future years is sensitive to assumptions concerning the incidence rates for birth cohorts after 1959. For fe males, the average historical mesothelioma rate was applied to all cohorts after the 1955-1959 cohort This assumption is not controversial because the trend for females has been virtually constant for the past 20 years. The projected numbers of male cases are based on stronger assumptions. To project beyond the 1955 1959 cohort, the downward male trend was continued by substituting the 1885-1889 birth cohort incidence rates for the 1960-1964 birth cohort and the average female rates for all subsequent cohorts. Different as sumptions about future rates could either increase or decrease the number of cases projected for the future or extend the time it will take to reach background levels. However, independent of the particular as sumptions selected, the characteristics of the trend would not change, with a peak around the year 2000 at approximately 2,300 cases, followed by a decline to -a constant background level. The analysis by Peto et al. (9) of mesothelioma in the United Kingdom indicates a peak around the year 2020. The difference between the United States and (:nited Kingdom results is a consequence of the timing of maximum exposure. Peto et al- report that maxi mum exposure in the United Kingdom occurred around 1970, whereas maximum exposure in the United States occurred from the 1930s to the 1960s. Considering the time period of maximum exposure, the subsequent downward trend in exposure, and the currently low exposure levels experienced by workers (5), the assumptions used to project the number of future US cases are reasonable. The US peak in cases occurring approximately in the year 2000, and the decline during the next 50-60 years toward 500 re flects both the US trend in raw asbestos consumption and reductions in workplace asbestos exposure levels over time. REFERENCES /. Nicholson 1W. Occupattonat exposure to asbestos, population at nsl and projected mortality (980-2030. Am 1 mi Mod 1982;3:259-3fl. 2. McDonald 7C. Health implications ofenvironmental exposure Am J Epidemiol Val. 145, No. 3, 1997 21S Price to asbestos. Envirou HealthPersp 1985;62:319-28. 3- Spinas R, Beebe G, Connelly R, et al. Recent trends in mesothelioma in the United States. Am J Ind Med 1986 9: 397-407. 4. Dupre IS, Mustard JF, Uffen RJ. Report of the Royal Com mission on matters ofhealth and safety arising from the use of asbestos in Ontario. Ontario, Canada: Ontario Ministry of the Attorney General, 1994. 5. Price B, Crump KS, Baird EC. 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I School Health 1982;August:358-64. 28. Bureau ofMines.. Asbestos in 1992. Washington, DC: United States Bureau ofMmes, 1993. (Bureau of Mines Annual Report-Mme Industry Surveys), 29. Occupational Safety and Health Standards; standard for expesure to asbestos dust. Federal Register. June 7, 1972;37: 11318-22. 30- Final rule for occupational exposure to asbestos, (remake, arithophyfite, and aclinolite. Federal Register. June 20,1986; 51:22612. 31. Final rule of occupational exposure to asbestos. Federal Reg ister. August 10, 1994;59:40964-1165. 32- National emission standards for hazardous air pollutants; as bestos, beryllium, and mercury. Federal Register. April 6, 1973;38:8820-3- Am J Epidermal Vol. 145, No. 3, 1997