Document k6DEpM4qM6RkKLNZp8kdMaLZO

AMERICAN JOURNAL OF INDUSTRIAL MEDICINE 31 :744-755 (1 997) Exposure Limits for UnconventionalShifts: Toxicokinetic and Toxicodynamic Considerations V. Fiserova-Bergerova, PhD,l* and J. Vlach, PhD2 Adjustment factors (AF)for inhalation exposure to chemical agents during unconventional work schedules were derived on toxicokinetic bases. AFs depend on the half-life of the agent and on the work schedule. Because they are grossly affected by cumulation, AFs were calculated for steady-state conditions. They were based on the following measures of chemical body burden: (1) end-ofshiB biological level as used previously by other investigators; and (2)areas under the curves, AUC,,, AUCh,, and AUCWeewbhich correlate with average biological levels during the shif, work day, and work week, respectively. The dependence of AFs on the half-life was studied on 50 possible work schedules using agents with a half-life of 1 hr to 2 years. Based on the data, simple equations suitable f o r j e l d conditions were derivedfor determination of AFs. Since AFs based on individual measures of body burden are not the same, the pharmacodynamics of the toxic endpoint should be considered when selecting the measure of body burden and the half-lifefor AF determination. Am. J. Ind. Med. 31:744-755, 1997. o 1997 Wiley-Liss,Inc. KEY WORDS: occupational exposures; TLF toxicokinetics; unconventional work shifts; body burden; chemicals INTRODUCTION Occupational exposure limits, such as TLV, MAC, and PEL, are time-weighted averages (TWA concentrations) of chemical air pollutants which are meant to provide health protection in work places with a conventional work schedule of 40 hrlweek (Le., 5 consecutive days of 8-hr shifts). For a short time, the TWA can be exceeded. The permissible excursion concentration is defined either by short-term excursion limits or by excursion factors derived on a statistical basis (i.e., on the probability that the TWA would be maintained) considering the toxicodynamics and serious.. ness of the health effect. Application of TWA exposure limits to industrial operations with extended shifts and unconventional shift cycles has been questioned.A formula for adjusting TWA exposure limits for unconventional shift cycles was tirst proposed by Brief and Scala [1975]. Their reduction factor, RF, is based on the ratio of exposure duration to nonexposure duration per week: w=-4.0- 168- N N 128 where N denotes the number of hours for which the worker is exposed during an unconventional work week. Numbers 40 and 128 represent the hours of exposure and nonexposure over a week of conventional shifts, and 168 represents the total number of hours per week. Toxicodynamic Approach 'University of Miami, School of Medicine, Miami, FL. 2University of Waterloo, Department of Electrical and Computer Engineering, Waterloo, Ontano. Canada. 'Correspondence to: Vera Fiserova-Bergerova(Thomas), Ph.D., University of Miami, Departmentof Anesthesiology,P.O. Box 016370,Miami, FL 33101. Accepted for publication 13 November 1996 OSHA recognized that development of the adverse effect plays an important role in the safety of exposure during unconventional shifts [OSHA, 19763. Based on simplified toxicodynamic assumptions, OSHA regulators pooled the chemical air pollutants into four categories: (1) ceiling (irritants and agents with PEL based on technologic feasibility), which does not require exposure adjustment for o 1997 Wiley-Lis, Inc. I i I ! -.--- Exposure Adjustment for Unconventional Work Schedules 745 unconventional work schedules; (2) acure, which requires the following adjustment for daily exposure: 8 Adjusted PEL = PEL -n [EPA, 19921 and hepatotoxicity, are related to the AUC during exposure (AUC,,,). AUC,,, reflects the average biological level during exposure. Finally, systemic adverse effects of agents with a very long half-life may best correlate with the dose related to AUC over the work cycle (AUCWeek). where n denotes the number of exposure hours (unconventional shift duration); (3) cumulative, which requires the following adjustment for weekly exposure: 40 Adjusted PEL = PEL -N An example is the dverse effect induced by saturation of binding sites, as in the case of nePhrotoxiCitY induced by exposure to some heavy metals [Lauwerys and Bernard, 19871. Figure 1 shows the dependence of the measures of internal exposure-concentration in blood and AUCs-on where N denotes the number of exposure hours during an unconventional work cycle; and (4) acute and cumulative, which requires adjustment for daily or weekly exposure, depending on which provides stronger protection. the duration of exposure and on the half-life of the agent. The sketch presented in Figure 1 (top) clearly shows that biological levels of agents with a short half-life level off during a conventional shift and remain unchanged if the shift is extended. By contrast, the AUC increases with h e exposure duration. The bottom sketch shows that the biologi- Toxicokinetic Approach cal levels and AUCs of agents with a long half-life slowly rise when the exposure is extended. i Mason and Dershin [19761 recognized that the rates of This paper derives and compares the adjustment factors rising and declining concentrations of inhaled agents in the for prolonged exposures to agents with health effects related body affect systemic toxicity; they related the chemical body to biological levels and AUCs. Exposures permissible burden to the biological levels of the chemical agent at the during a conventional work schedule, multiplied by the end of the last shift of the work cycle. They also acknowl- derived adjustment factors, represent a toxicokinetic equiva- edged the dependence of the safety factor on the half-life of lence to exposures permissible during a conventional work the uptake and elimination of the agent. Based on toxicoki- schedule. netics, they proposed a multiexponential equation for predict- ing cumulation of the inhaled agents in the body over an METHODS unconventional work cycle. Hickey et al. [1977,1979,1980] and Roach [1978] further elaborated on these ideas and Equipment applied the toxicokinetic concept to a variety of working situations. Andersen et al. [19871 used the physiologically This work involved the use of an IBM personal based pharmacokinetic model to evaluate the occupational computer and Matlab software (The Math Works, Natick, risk of exposure to some organic solvents. The toxicokinetic MA, 1992). models were comprehensively reviewed by Paustenbach [ 19851. MathematicalApproaches Measures of Chemical Body Burden The systemic effects of xenobiotics (toxic substances, drugs) correlate better with their internal dose than with their external dose. The measure of internal exposure can either be the concentration of the agent in the blood, or the area under the curve (AUC) depicting the concentration of the inhaled agent in the blood during and after exposure. The adjustment factor for individual ag-ents should be based on the measure exhibiting the best correlation with the toxic endpoint. Some adverse effects, such as diminished vigilance, analgesia, and imtation, are related to the biological levels at the target site and thus to the highest concentration of the agent (or metabolite) reached in the blood. The end-of-shift biological level has therefore been used as the criterion for establishin-g the safety factors for these ag-ents. The majority of toxic endpoints, such as carcinogenicity It is assumed that the airborne concentration of the agent during the shift is constant, and that the permissible concentrations are so low that first-order kinetics apply to all processes, including metabolism and binding. According to our experience, most TWA exposure limits comply with these assumptions [ACGIH. 1992; Commission for Investigation ... , 19951. Single exposure At low inhalation exposures, when first-order kinetics apply. the rise and declineof biological levels of the agents during and following exposure are described by two exponen- tial functions. The rising of the biological is described by Equation ( ): Z(t) = Z,e-k' + C(1 - e-kt) (1) 746 Fiserova-Bergerova and Vlach I tH = lhr agent which can be reached at the given airborne concentration. The rate constant k is related to the elimination half-life. tl,?: If the duration of the shift with exposure is denoted by x i ,and the duration of the post-shift period without exposure is denoted by yI, Equations 1 and 2 can be rewritten as follows to calculate the biological level at the end of the shift: +Z2 = Z,e-kxl C(1 - e-"!) (4) and at the end of the post-shift period: Intermittent exposure Biological levels at the end of the shift on the ithday of the work cycle (GI)and before the next shift can be calculated using Equations (6) and (7). End-of-shift level: +&, = Z2,-ie-"~ C)(1 - e-"]) (6) Prior-shift level: Z2,+1=Z21e-ky1 (7) tlA = lOOhrs .2 0 I 16 24 HOURS AFI'ER =ART OF ExposuRE FIGURE 1. Schematic picture of dependence of biological levels, AUC, and AUCm on the half-life of the agent and duration of the exposure.Biologicallevels, expressed as fractions of the steady state levels, are plotted against time. In the examples given, the exposures lasted 8, 12, or 16 hr. The dotted lines separate AUCs during exposure (AUC,) and following exposure (AUCd). Biological levels during intermittent exposures can be calculated for any day by using Equations (6) and (7) in sequence, starting with i = 1 and substituting the parameters for the first work day, then with i = 2 and substituting the parameters for the second work day, and so forth, until, for the last day of the work cycle, i = n, where n denotes the number of days in the work cycle. If the circadian cycle is maintained, y, = 24 - x,. The fluctuation of biological levels during a conventional work week is pictured in Figure 2. To account for weekends and other days without exposure, C for such days equals zero. Steady state The declining of the biological level following the offset of exposure is described by Equation 2: Z(t) = (2) In these equations, Z(t) denotes biological levels as a function of time t, Z1is a possible residue from the previous exposures, Z2 is the biological level at the end of exposure (Fig. 2), and e is the base of the natural logarithm. C, which is directly related to the average exposure concentration (TWA), represents the maximum biological level of the If the cycles of intermittent exposures are repeated, cumulation rate over repeated work cycles declines until the steady state is reached. At that time, the biological levels at the beginning and end of the cycle are the same (ZZnil= ZI) and the cycle of biological levels is repetitious. Biological levels in a cycle composed of n days is described by a set of 2n linear equations with 2n unknowns denoted by Z,. Numerical solution of these equations is easy when using a computer [Mason et al., 1976; Hickey et aL.1977; Roach, 19781. We used the Matlab program because of its graphical capabilities. I I Exposure Adjustment for Unconventional Work Schedules 747 FIGURE 2. Schematic representation of an intermittent weekly exposure. The symbols, also used in the equations, are explained in the text. Areas under the curves Once the biological levels at steady state have been calculated, the areas under the curves (AUC) depicting the rising and declining of biological levels can be calculated by integrating Equations (1) and (2). The AUC d uring any shift orin the work cycle (denoted by subscript i) is: AUC,,,~ = [&i-,e-kt + C(l - dt cx, + c-2 2 1 - 1 = k - e-kxi) (8) orSimilarly, AUC during the resting post-shift period is: AUC,,,, = ZZle-kdt t = z-21(1 - e-'yi) k (9) shift in the conventionalcycle are the most critical, the ratios of the parameters were determined on a daily basis. Since AFs are ratios of linear functions, they are independent of exposure concentrations and, for simplicity,C = 1was used in calculation. For unconventional work schedules, the exposure bioequivalentto the permissible exposure limits is calculated by multiplying the permissible exposure concentration (e.g., PEL, TLV, or MAC) by the adjustment factor. RESULTS A N D DISCUSSION The calculations of adjustment factors presented above are a refinement of previously published studies proposing TABLE 1. Weekly Work Cycles Used in the Examples. Duration of Shifts intiours The daily areas under the curves, AUCday,la,re calculated as the sum of AUC,,,> and AUC,,,. The weekly areas are calculated as the sum of daily AUCs. The areas are directly related to the mean (TWA) biological levels during the shift (AUC,,,), during the day (AUCday).and during the work week (AUC,k). Week day: work schedule l I1 111 W V VI VI1 Conventional schedule 888 8 800 Adjustment Factor To determine the bioequivalents of exposures during conventional and unconventional shifts, four measures of body burden calculated for steady-state conditions were compared: (1) peak biological levels (end-of-shift levels); (2) average biological levels during the shifts (AUC,,,); (3) average biological levels during the day (AUCd,,): and (4) average biological levels during the week (AUCmeekT).he adjustment factors (AF) were determined as ratios of values of individual parameters calculated for conventional and unconventional shifts. Unless indicated otherwise, the AFs were calculated by dividing the biological level (or AUC) derived for the 5th day of the conventional work cycle by the same parameter derived for any day of the unconventional schedule. To determine whether the AFs based on the last 40 hrs/week 48 hdweek 64 hdweek Unconventionalschedule A 10 10 10 1 0 0 0 B 0 10 10 10 10 0 C 12 8 0 12 8 0 D 8 12 0 8 1 2 0 E 0 0 16 1 6 8 0 F 0 0 8 16 16 0 G 16 0 0 1 6 8 0 H 0 12 12 12 12 0 I 12 12 0 12 12 0 J 0 0 16 16 16 0 K 16 0 16 0 1 6 0 L 16 16 0 16 16 0 M 0 16 16 16 16 0 The between-shinperiods = 24 - shin hours 0 0 0 0 0 0 0 0 0 0 0 0 0 748 Fiserova-Bergerova and Vlach - .6 It I,' .6 I I 13 I# I# I t I# I# d I# 1.6 AUCfi4 I -JW-I- - - _ _ /--.6 I+ l# 13 13 If 1.6 1.4 . J.4 . 1.3 . 1.0 I .a- .6 It ' IJ ' .' 1.b - - _ _ _ _ _ _ _ _ - - - - - - - - .I .# 1 .6 I,' 13 I,' I t I t tH in houn d 13 1 3 I If FIGURE 3. Dependence of adjustment factors (AF)on the half-life (tin) of the agents. Comparison of AFs for the first work week with AFs at steady state. AFs, based on biological levels at the end of the shifts, AUC, and AUC-,, are calculated for the first work week (left) and for the steady state (right). The unconventional work week consists of four consecutive days with 10-hr shifts followed by three days off. AFs for the first shift are calculated as a ratio of the values calculated for the first shifts of the conventional and unconventional work week. AFs for other shifts are similarly calculated. 1st unconventional shift: 2nd unconventional shift: . , . . , , ; 3rd unconventionalshift: - - - - -; 4th unconventionalshift:-. exposure adjustment for unconventional work cycles based on the toxicokinetic prediction of end-of-shift biological levels at steady state: (1) the effect of cumulation on AFs is observed by comparing the AFs derived for the first work cycle and for the work cycle at steady state; (2) calculation of biological end-of-shift levels, AUC,,,, and AUC&,,, for each shift of the work cycle, allows identification of the shift inducing the largest body burden during conventional and unconventional work schedules (reference shift and critical shift, respectively); (3) the AUCs during the shift (AUC,,,), during the work day ( A X d a y ) a, nd during the work week (AUCWeek)w, hich correlate with TWA biological levels during the shift, day, and week, respectively, are considered as alternative bases for determination of AFs; and (4) the measures of body burden used for determination of AFs are related to the toxic endpoint of the agent. Our conclusions on the effects of cumulation, measures of chemical body burden, and work schedules on AFs of agents with a different half-life are based on the study of 50 different work schedules. The typical findings are demonstrated ! t Exposure Adjustment for Unconventional Work Schedules 749 1.1 1.4 1.1 1.0 .a .6 1.6 14a 1.4 1.1 I' OPTION 1 OPTION 2 End-o/-sh@ bwlogicd levels 1.6 I 1.4 -, .I . 1.1 1.0 .# AUC - 8, I# I,' . .. . I,' It 1.4 ,' '\ '' '. \ 1.2 .6 1 I# 11.6'I 1.4 I,' d 1 I .s -' . I# 13 13 I# I# I# 13 I,' 1 1%in hours FIGURE 4. Additional options for calculation of adjustment factors. As in Figure 3, the example uses four 10-hour shifts, but the work week starts with a day off (work schedule 8 in Table I). Option 1(/e@: AFs for all three measures of body burden are ratios of values calculated for the second shift in the conventionalwork week and first shift of the unconventionalwork week, and so on, as indicated by columns in Table I. Option 2 (right): All AFs are ratios of values calculated for the last shift of the conventionalwork week and indicated shifts in the unconventionalwork schedule. 1st unconventional shift: _.-._._;2nd unconventional shift: . . . . . . ; 3rd unconventionalshift: - - - - -; 4th unconventional shift:-. on 13 examples whose schedules are shown in Table I. In these examples, the 7-day cycles and circadian rhythm are maintained so that the cycle duration W = 168hr and y, = 24 - x,. Effect of Cumulation on Adjustment Factors The effect of cumulation on AF for agents with a different half-life is demonstrated in Figure 3 by using an unconventional work cycle of four consecutive days with IO-hr shifts followed by three days off (schedule A in Table I). AFs for all shifts during the first work week are almost the same. They indicate an increased risk of prolonged exposure to slowly eliminated agents. During repetitious work cycles, cumulation reduces the effect of shift prolongation. At steady state, AFs for individual shifts differ, the most apparent differences being exhibited by agents with a half-life of 10-200 hr. In the 750 Fiserova-Bergerova and Vlach OPTION 1 OPTION 2 End-o/-sh@ biological kveh .I .2 .- A U C b 1.4 1.4 r I II I. I -t 1 -4 1 .I .2 1 A I+ 1J I 3 I# I f I# I# 18 13 I f ts in hours FIGURE 5. Finding the critical shift. This example of combination of 8-hour and t2-hour shifts (work schedule C in Table I)documentsthat the last (fourth)shft in the unconventional work schedule is not always the critical shift requiring the largest adjustment. The AFs are calculated for Option 1 (lefl side) and Option 2 (rightside). For further explanation see Figure 4. given example, when shifts of equal duration are on consecutive days, the largest adjustment is indicated for the last shift of the work week (full lines in Fig. 3) and the smallest adjustment is indicated for the first shift (broken lines in Fig. 3). AFs for agents with very long half-lives are the same. In the example, no exposure adjustment is indicated for slowly eliminated agents if the toxic endpoint is related to the end-of-shift biological level or to the daily TWA biological level (AUCday).For agents with a very short half-life, no adjustment is needed if the toxic endpoint is related to the end-of-shift biological level, but an adjustment of 0.8 (8/T) is indicated for agents with a toxic endpoint related to the TWA levels (AUC,,, and AUCday)T. he largest adjustment is needed for all agents with a toxic end-point related to AUC,,,. In the given example with 40-hr work weeks (the same as in conventional work week), AF based on AUCweekequals 1. Conclusions With the exception of agents with a short half-life, the AFs calculated for the first work cycle are smaller than those calculated for the steady state. As a result of cumulation, biological levels (and AUCs) increase, and the differences between conventional and unconventional work schedules diminish. In an occupational setting, adjustment for repetitious exposures is crucial. Therefore, the rest of this Exposure Adjustment for Unconventional Work Schedules 75 1 SCHEDULE H SCHEDULE L End-O/-rlru)bidoglccJ kve& 1.4 I I _ _.2 Id .I#. 13 I# I f I t I# AUC 1.4 I ' T4r 13 13 I# I t-4 i -4t I FIGURE6. Extended weekly working hours. Option 2 was used to calculated AFs for a 48-hour work week consisting of four 12-hour shifts on consecutive days and a 64-hr work week consisting of four 16-hr shifts with a day off after the second shift (Schedule H and L In Table I). Note that all AFs for slowly eliminated agents equal 40M. the exception being AUC,. 1st unconventional shift: unconventional shift: . . . . . . ; 3rd unconventionalshift: - - - - -;4th unconventionalshift:-, 2nd discussion concentrates on the AFs for steady-state conditions. Reference Shift Figure 3 relates four shifts in the unconventional work week to the first four conventional shifts. The last (fifth) shift of the conventional work week (which exhibited the highest body burden) was not used for determination of AFs. There are two other options for AF determination: In Option 1, if the same unconventional work week starts with 1 day off (work schedule B in Table I), the AFs for the first unconventional shift are based on the second conventional shift, etc. as indicated by the columns in Table I. In this option, the first conventional shift is not used for determination of AFs but the last conventional shift is used for calculation of AFs for the last unconventional shift. Option 2 uses the last (fifth) shift of the conventional work week as the reference shift; this shift exhibits the highest values for all measures of chemical body burden (Fig. 2). In Figure 4, AFs are compared using Option 1 (left side) and Option 2 (right side). In the given example, the largest adjustment is indicated for the fourth (last) unconventional shift, regardless of the body burden measure or option used. Contrary to work schedule A (Fig. 3), the AFs exceed 1 for the first two shifts of the workweek if the agent has a 752 Fiserova-Bergerovaand Vlach TABLE II. Estimation of Adjustment Factors Based on Four Measures of Body Burdena Largest reduction t l n C 4 hrs tin tlR > Inflectionb 20 days Parameters Biol. levels AF1 1 (hrs)c 6-18 AFz tin(hn) -+ 40W 80 100 M3 ~~ 40MI AUCexq 8/l 3-14 8 / T , 1 6 ( l + t ) 70-100 W.40MI AUCm 8I-r 8IT 50- 100 40MI AUGVWk 40MI 40MI None 40MI a&?nts are characterizedby half-life (tli2)W. ork schedulesare basedon weekly work cycle and circadian cycle. blndicatesthe half-lie of agentsfor whichAF = (AF, + AF,)/Z. The inflectionpointdepends on the work schedule. It appears at the shocter tln if a day off is inserted between the prolongeds h i i . Clndicatesthe rangeof half-lifeof the age& with the smallestAF,. AF = adjustmentfactors. T = durationof the longestshiinthe week (inhours).t = duration of the shii precedingor followingthe longestshift. fall s h i i are of the Sameduration, then t = T.W = number of workinghours'week. half-life in the range of 10-200hr. Comparison of Figures 3 and 4 indicates that the smallest adjustment is needed if AFs are based on Option 2 (last conventional shift). AFs for schedules A and B are the same when Option 2 is used. Conclusions In an unconventional work week, some shifts exhibit an AF larger than one, some an AF smaller than one, depending on the work schedule and half-life of the agent. Permissible exposure limits comprehend safety of the last shift in the conventional work week. This shift exhibits the highest values of the end-of-shift biological levels as well as TWA biological levels (AUC,,, and AUC,). Therefore, use of the last shift of the conventional work schedule as a reference shift is permissible. It is unambiguous in cases with complex, irregular work cycles. The last shifts were also used as a reference shift in the previous studies [Mason et al., 1976; Hickey et al., 1977, 1979; Roach, 19781. Critical Shift The critical shift in the work week is the shift which requires the largest adjustment, i.e. the smallest AF. In the previous schedules, when shifts of equal duration occurred on consecutive days, the smallest AFs were indicated for the last shift in the work week. This was not always the case if the schedule consisted of shifts of unequal durations with a day off between. An example is shown in Figure 5, using work schedule C in Table 1. In this example. consisting of two 12-hr shifts each followed by 8-hr shifts and a day off, all three body burden measures require a larger exposure adjustment for the first and third shifts than for the last (fourth) shift. In this example, which maintains the 40-hr work week, no exposure adjustment is indicated for any shift with exposure to agents with a half-life longer than 200 hr and toxic endpoint related to end-of-shift biological level, AUCdar and AUCWeekA. significant exposure reduction, however, is indicated for the first and third shifts with exposure to agents with a long half-life and toxic endpoint related to AUC,,, (AF = 8/12 = 0.666). Conclusion The last shift of an unconventional work week is the critical shift if the work schedule consists of shifts of equal duration on consecutive days. If the shift duration is unequal or a day without exposure is inserted between working days, the longest shift (or the shift prior to the day off) may be the critical shift. For agents with a long half-life, the AFs for all shifts in the cycle approach the same value, with the exception of AF based on AUC,,,. The extent of adjustment varies for individual measures of body burden and work schedule. Effect of Weekly Work Hours on AFs Figure 6 presents two examples of work weeks with 48 hr (four 12-hr shifts on consecutive days) and 64 hr (four 16-hr shifts with a day off after the second working day), respectively (Schedules H and L in Table I). Conclusions The shift duration mainly affects AFs of agents with a short half-life, while AFs for agents with a long half-life are affected by the number of working hours per week (AF = 40Mr). AFs for agents with a half-life of 10-200 hr must be calculated individually. AFs based on AUCweekare always equal to 40m, regardless of the working schedule or the half-life of the agent. Estimationof Adjustment Factors The calculation of AFs, described above, is complex, and difficult to perform in field conditions. To simplify the calculation, essential AFs were estimated based on curves similar to those shown in Figures 4-6. Curves calculated for 50 unconventional work cycles were analyzed. Table I1 shows the formulas for estimation of AFs for agents with a very short half-life, ti/? <4 hr (AF,)a,very long half-life, ts >20 days (AF,), and those requiring the largest adjustment (AF:). The table also shows that the largest adjustment is needed for agents with a half-life of 3-18 hr. The inflection point of the half-life provides guidelines whether AF?,AF3, or the mean of both should be used. I i Exposure Adjustment for Unconventional Work Schedules 753 TABLE 111. Exposure Limits for Unconventional Shifts:Comparison of Calculated and Estimated Adjustment Factorsa Short half-life Bil. Scheduleb level AUCs 8I-r long half-life level and AUCw 4O/W Aut, 8/T*4O/W Largest reduction Biol. level '/&/T+4O/W) AUCexp 8/T*16/IT+t) W = 40 hr T = t = 10 hr A, B 1 1 .80 .80 1.00 1.00 .80 .80 .90 .84 .64 ,155 T = 12 hr, t = 8hr C 1 1 .67 6 7 1.00 1.00 .67 .67 .83 .86 .53 .56 D 1 1 67 .67 1.00 1.00 .67 5 7 .83 .83 .53 .54 T = 16hr,t = 8 hr E 1 1 .50 .50 1.00 1.00 50 .50 .75 .66 .33 .29 F 1 1 .50 .50 1.00 1.00 .50 .50 .75 .64 .33 .28 G 1 1 .50 .50 1.00 1.00 S O .50 .75 .76 .33 .37 W = 48 hr T = I = 12 hr H 1 1 .67 5 7 .83 .83 .56 56 .75 .73 .44 .& I 1 1 .67 .67 .83 .83 .56 .56 .75 .78 .44 .49 T = t = 16 hr J 1 1 .50 .50 .83 .83 .42 .42 .67 5 1 .25 27 K 1 7 .50 .50 .83 .83 .42 .42 .67 .75 25 .37 W=64hr T = t = 16 hr L 1 1 .50 .50 .62 .62 .31 .31 .25 .26 .56 .57 M 1 1 .50 .50 .62 .62 .31 .31 .25 .29 .56 .64 -mated values (italicized nu-) were calculated usingthe above equations. The preceding (nonitalicized) numbersare values calculated as explainedintext under MathematimlApproaches. Wters A-M denote wwk schedulesof unconventionalshifts as citedintext and show in Table I.Other symbolsare the same as inTable II. Differences between calculated and estimated values, shown in 13examples in Table 111, indicate that the accuracy of the estimates meets the requirements of field studies. Adjustment Factors in Other Studies Table VI compares AFs derived in this paper with those derived by other investigators.Table VI shows that the AFs derived in this study, and those derived by Roach [ 19781,are significantly larger then the reduction factors proposed by Brief and Scala [ 19751. Neglect of the toxicokinetic profile of the agent leads to overprotection. As expected, the AFs based on biological end-of-shift levels in this study agree with the values calculated by Roach [ 19781. Adjustment factors for exposure reduction can be based on one of the four measures of body burden. The AF based on body measure best related to the toxic endpoint should be used. AFs derived for different measures of chemical body burden were compared with OSHA's recommendation [19761 for exposure adjustment based on an empirical toxicodynamic approach (Table VI). Adjustment factors based on biological end-of-shift levels of rapidly eliminated agents support OSHA's recommendation for agents with ceiling exposure limits. The adjustment factors based on the AUC*,, support OSHA's recommendation for agents with acute toxic effect. These AFs should also be applied to carcinogens [EPA, 19921which OSHA classifies as agents with exposure 754 Fiserova-Bergerovaand Vlach I TABLE IV. Half-lives of Organic Compounds TABLE V. Half-Lives of Metals and Other Inorganic Compounds Compounda llnof parent tlR of Days Months Years compound Urinary metabolite As (urine) 1 3.5 8 Min Hr Days metabolite Hr Days Cd (blood) 3.6 10 (Urine) 0.5 2.7 10-30 Solvents, and other volatile, hydrophobic agents Benzene 25 2.5 1.25 Phenol Co (blood) 0.5 2.7 6 1.2 (urine) 2.0 1.4 Enflurane 18 3.2 1.5 Fluoride Org. fluorine 1.6 F 3.7 (urine) (bones) 0.25 1.5 Ethylbenzene 3 1.5 2 Mandelic ac. 5 1 Hg Halothane 40 5 1.25 TFAA 2.33 n-Hexane 8 1.7 2.1 Hexanedione 14 lsoflurane 9 2 0.73 pb Methykhlorofm 60 5 1.3 TCAA 3 TCE 1 1 (plasm) (e*.) (urine) (Mood) (Urine) 10 28 3.5 7 27 5.7 40 40 6 40 1 20 MEK (ur) MlBK 30 1.35 20 1.25 0.25 tlR from ACGIH, 1992. (ur) 4 0 7 Perchloroethylene 15 4 4 TCAA TABLE VI. Comparisonof Adjustment Factors in 4 Studies. 3.3 UnconventionalWeekly Cycles of 10-Hour Shifts on ConsecutiveDays Styrene (bl) 30 12 3 Mandelic ac. 3.5 and Between-Shift Periods of 14 Hours Toluene 26 3.7 3.2 Hippuric ac. 2 0-Cresol 3 Shm This paper Trichloroethylene 20 3 1.25 TCAA 3 per tm Brief & i TCE 19 week Gxg AUC, AUC- A& Roach Scala OSHA* Xylene 60 20 Methylhip. ac. 3.6 1.25 Other organic agents, low volatile, hydrophilic Acetone 3 3.5 (ur) Aniline 3.5 30 p-Aminophenol DMF MMF Furhrral Furoic ac. Methanol (ur) 2.0 Formic ac. Phenol (ur) pep (w) 3 0.4 3,7 2 2.25 3.5 1.2;72 4 6 1 1.00 .77 .80 1.00 1.00 1.00 1.00" 10 .85 .66 .EO 1.00 .85 1.00 .8ob loo0 1.00 .80 1.00 1.00 .99 . 1.00 1.w 1 1.00 .77 .80 .80 1.00 .74 1.00" 10 .85 .65 .80 .80 .85 .74 .8ob loo0 .80 .64 .80 .80 .EO .74 .8oc 1 1.00 .77 .80 .67 1.00 .56 1.00" 10 35 .65 .80 .67 .85 .56 .8@ 1oo0 .67 .54 .67 .67 .67 .56 .67c i L I Weasured in exhaled air unless indicated otherwise. tIR of industrial agents from ACGIH 119921;t,R of anestheticagents from Holadayet al. [1979]and Fiserova-Bergerova[1992]. ur, urine: bl, blood. limits based on technologic feasibility. Adjustment factors based on the AUCWeeskupport OSHA's recommendation for agents with chronic effects. Determination of Half-Lives of Chemical Agents The half-lives of organic compounds and of metals listed in BE1 documentations [ACGIH, 19921 are shown in Tables IV and V, respectively. The half-lives of chemical agents can be determined experimentally from the elimination curves of the agent or its metabolite. The half-lives of volatile solvents can also be predicted from the physicochemi- &:Adjustment factor for agents with toxic endpoint related to biological end-of-shift level (instant toxiaty). AUC:, Adjustment factor for agents with toxic endpoint related to time weighted average level during the shift (acute toxic@). AUC,: Adjustment factor for agents with toxic endpotntrelatedto time weightedaverage levelduring the day (subchronictoxic@). A h : Adjustment factor for agents with chronic toxicity. 'Adjustment factas recommended for ceiling (a), acute (b), and chronic effects (9. respectively.(Independentof the half-life). cal properties of the agent and the physiological parameters of the exposed subjects [Fiserova-Bergerova et al., 1974, 19801. Half-lives of volatile hydrophobic solvents indicate triphasic uptake and elimination, with no half-life exceeding 4 days. The occupational exposure limits for some solvents are based on irritation or reduction of vigilance and other CNS functions. These effects are related to the fast compartment, that is, to the shortest half-life (Table IV). No exposure adjustment, therefore, is needed. However, if the toxic endpoint is related to the TWA biological Exposure Adjustment for Unconventional Work Schedules 755 level during the shift, day, or week, the adjustment factor can be estimated using an appropriate equation from Table based on the appropriate AUC should be used. If the target 11. To calculate the toxicokinetic equivalent for unconven- toxic endpoint is not identified, the smallest AF should be tional shift, the exposure limit permissible for conventional used. work week is multiplied by the appropriateAF. Table V shows very loilg half-lives for all metals. Therefore, an adjustment based on the AUCWeeiks appropri- REFERENCES ate. (AF = 40/working hours per week). Significance of Exposure Adjustment for Unconventional Work Shifts American Conference of Governmental Industrial Hygienists ( 1992): "Documentation of the Threshold Limit Values and Biological Exposure Indices." Vol. 111. Cincinnati, OH. The work schedule is not the only factor affecting the chemical body burden. Dermal absorption and physical Andersen ME. et al. (1987): Adjusting exposure limits for long and short exposure periods using a physiological pharmacokinetic model. Am Ind Hyg ASSWJ 481335-343. workload significantly increase the internal dose. Moreover, Astrand I (1983): Effect of physical exercise on uptake, distribution and I increased alveolar ventilation and increased tissue perfusion elimination of vapors in man. In Fiserova-Bergerova V (ed): "Modeling of Inhalation Exposure to Vapors: Uptake, Distribution and Elimination." Vol. during strenuous physical activity result in shortening of the 11. Boca Raton, FL: CRC Press, pp 107-1 30. half-life [Fiserova-Bergerova, et al., 19801. The exposure limits are usually set for a light or moderate workload with Brief RS, Scala RA (1975): Occupational exposure limits for novel work schedules. Am Ind Hyg Assoc J 36:467471. minute ventilation of 20 Wmin. Pulmonary ventilation doubles with a heavy workload. [Astrand, 1983; Fiserova- Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (1995): "List of MAK and BAT Values 1995." Bergerova 19951. This means that the dose inhaled at a Report No. 3I. VCH Verlagsgesellshaft,Weinheim, Germany. heavy work load can more than double, thus calling for adjustment by a factor of about 0.5. The same adjustment is most likely the largest exposure reduction required for an EPA Request for Comments on Draft Report on Cross-Species Scaling Factor for Cancer Risk Assessment (1992): 57 FR 24152, June 5, 1992. Washington, DC:Bureau of National Affairs, pp 590-6 11, unconventional work schedule in an occupational setting. It Fiserova-Bergerova V (1992): Inhalation anesthesia using physiologically is believed that the exposure limits have safety factors that based pharmacokineticmodels. Drug Metab Rev 24531-557. afford protection during a heavy workload and moderate Fiserova-Bergerova V (1995): Extrapolation of physiological parameters dermal exposure. On this supposition, exposure adjustments for physiologically based simulation models. Toxicol Lett 79:77-86. for unconventional shifts seems to be unnecessary unless the Fiserova-Bergerova V, et al. (1974): Simulation and prediction of uptake, work schedule is extreme. distribution and exhalation of organic solvents. Br J Ind Med 31:45-52. CONCLUSIONS Unconventional work schedules increase the risk potential of adverse effects. But unconventional schedules, unless the exposures are extremely long, increase the risk potential less than twice (AF ?OS), thus keeping the range of increased risk within the range induced by physical stress of workload and dermal exposure. In the case of exposures under physical stress of workload, reduction of the exposure is not called for, because, it is believed, the safety factor incorporated in the permissible exposure limits protects the exposed worker against the increased uptake induced by the workload. It can be assumed, therefore, that there is no need for exposure adjustment for unconventional work schedules, except in extreme conditions, such as when working hours are more than doubled. In the case of extreme conditions, the exposure concentration should be reduced. 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