Document B5JzQX0yVg2oeBknopy9Nb7Q8

Pergamon ... . .... ..,~., ., . . ., r r . . ..., ... . C 1997 British Oaupational Hygiene Society. AI1 nghts reserved Published by Elxvier Science Ltd Rintcd in Great Bntain M o 3 4 7 8 / 9 7 117.00+0.00 PII: S0003-4878(96)00180-9 TIMING OF SAMPLE COLLECTION FOR BIOLOGICAL MONITORING OF OCCUPATIONAL EXPOSURE Vera Fiserova-Bergerova* and Jiri Vlacht *University of Miami, Department of Anesthesiology, Miami, Florida, U.S.A.; and tuniversity of Waterloo, Department of Electrical and Computer Engineering, Waterloo, Ontario, Canada (Received 24 July 1996) Abstract-The timing of sample collections for the biological monitoring of occupational exposure profoundly affects the resulting data. Sampling time with respect to the day in the working week and the end of exposure is crucial for measurements of rapidly excreted indicators of exposure. Owing to the cumulation of slowly excreted exposure indicators, timing of sample collection with respect to the duration of employment is essential. The steady state is established within a week, if the exposure indicator is excreted rapidly (with a half-life shorter than 45 h), or within months or years, if it is excreted slowly. In this study, exposure indicators are characterized by the elimination half-life. A monocompartmental model is used to calculate the biological levels at steady state and the duration of occupational exposure needed to reach the apparent s:eady state. 8 1997 British Occupational Hygiene Society. Published by Elsevier Science Ltd In the biological monitoring of occupational exposure, the timing of specimen collection profoundly affects the resultant data. For exposure indicators with rapid elimination, the timing of sample collection in relation to the beginning and/or end of the exposure is crucial. Selection of the sampling day can be also critical because of the cumulative effect of previous exposure during the week. The sampling times of biological specimens for measurements of rapidly excreted metabolites, with elimination half-lives of a few hours, such as phenol, hippuric acid and mandelic acid, are properly included in the definition of the reference values for each of these exposure indicators (BEI, BAT). When the half-life is so short that the timing cannot be controlled in field conditions, biological monitoring is unsuitable. Such is the case with the monitoring of organic solvents in exhaled air collected during the first hours following the end of exposure, when the half-life is only a few minutes. The rising of biological levels over months and years due to cumulation should be considered whenever biological specimens are intended for measurements of exposure indicators with a long half-life. For biological monitoring of some metals (with half-lives of years), a `waiting period' is suggested (American Conference of Governmental Industrial Hygienists, 1991; Deutsche Forschungsgemeinschaft, 1995), but no general guidelines were found for sampling biological specimens in order to monitor exposure indicators with a long half-life. `Address correspondence to Vera Fiserova-Bergerova (Thomas), University of Miami. Department of Anesthesiology, P.O. Box 016370, Miami, FL 33101, U.S.A. Fax: (305) 243-6425. 345 346 V. Fiserova-Bergerova and J. Vlach In this study, a monocompartmental toxicokinetic model was used to determine how long it takes to establish the apparent steady state during occupational exposure. The information is used to determine the minimum length of a worker's employment after which the reference values can be properly applied. METHODS The exposure indicators are characterized by the elimination half-life. The computations were performed in double precision, using an IBM personal computer. Mathematical approaches Single exposure. Biological levels at the end of exposure ( A )and at the end of the resting post-exposure period ( B ) are described by the following exponential equations: +A = Boe-kX C(1 - e-kx) (1) B = A e - b = Boe-k(x+Y)+ C(e-kY e-k(x+Y)) (2) where x and y denote durations of the exposure and post-exposure resting periods, respectively; k is a rate constant related to the half-life ( k =ln2/tl,2); Bo denotes the residue from previous exposures (which, in this case, equals zero); and C is the biological level that will be reached if the given exposure lasts infinitely. Occupational exposure. In a conventional work schedule, daily exposures lasting 8 h are followed by a resting period of 16 h, with the exception of the fifth postexposure period which lasts 64 h. The biological levels at the ends of shifts, Ai, and of between-shift periods, Bi, are described by the following equations: AI = + C(1 - e-8k)BI = B0e-24k+ C(e - - l a -e-24k) (3) A2 = + C(1 - e-'&) B2 = Ble-24k+ C(e-'6k- e-24k1 (41 + +AS = B4e-8k C(1 - e-8k)BS = B4e-l" C(e-64k- e-72c) (7) The indexes denote the sequence of shifts during the work week (Fig. 1). In general terms: Ai = Bi-le-8k+ C(1 - e-8k)Bi = + C(e-'6k- e-24k) (8) The exception is the calculation of B5, for which the exponent has to be modified in order to include the weekend period [Equation (7)]. The biological levels at the end of the shifts, and prior to the shifts, are obtained a 348 V. Fiserova-Bergerovaand J. Vlach To investigate the establishment of the steady state of exposure indicators with different half-lives, the computation of weekly cycles begins by substituting zero for Bo in Equation (3). In succeeding cycles, B5 from the immediately preceding cycle is substituted for Bf,. The computations are repeated until the difference between BO [Equation (IO)] and [Equation (1 I)] is acceptable. The biological levels at steady state, and the number of weeks needed to reach the apparent steady state, were computed for exposure indicators with half-lives between 1 h and 2 years. The computations were done for biological levels equal to the following percentages of the steady state levels: 99.99, 99.9, 99, 90, 75 and 50% (further referred to as `apparent steady state'). RESULTS The number of working weeks (length of worker's employment with the same exposure) needed to reach a selected percentage of the steady state level is shown in Fig. 2. The relation between the half-life and the number of weeks needed to reach the apparent steady state is described by a logarithmic function: log(w) = a log(tl/2) - 4 (13) where w denotes the number of weeks of the worker's employment, with exposure, needed to reach the apparent steady state, a is a slope which is equal to 1, and q is a constant dependent on the definition of the apparent steady state (Table 1). Half-life t l / 2 is given in hours. The number of weeks required to reach the steady state is independent of the exposure concentration as long as the concentration is in the range of linear kinetics. Permissible occupational exposures usually meet this requirement. The third column in Table 1 indicates the longest half-lives which allow the reaching of the apparent steady state in the second working week. It is calculated as an antilogarithm of q in Equation (13) (for w = 1, and a= 1, log tl12 = q ) , and pictured as x-intercepts in Fig. 2. For the purpose of biological monitoring, biological levels equal to 90% of the steady state level are acceptable. Thus exposure indicators with a half-life shorter than 45 h reach the apparent steady state during the second week of exposure. Exposure indicators with a longer half-life require months or years of occupational exposure to reach the apparent steady state. DISCUSSION It is known that, for rapidly excreted indicators of occupational exposure, the timing of specimen collection with respect to the beginning and the end of exposure is crucial. This study shows that the length of employment significantly affects biological levels of slowly excreted exposure indicators. Biological levels of exposure indicators with long half-lives rise over weeks, due to cumulation. The rising ceases at the steady state, when the weekly cycle of biological levels repeats itself. Because of the large variability of biological levels induced by environmental factors and by the physiological parameters of the exposed workers, sampling for biological monitoring is acceptable when the biological level reaches 90% of the steady state 1o m IC 8 1 Timing of sample collection 349 99.99% / 99.98 /. ../ 1. . x , /I: 1 , , , , , . , , : I O I 00 loo0 10.000 tIn(hrs) Fig. 2. Dependence of the number of working Weeks required to reach apparent steady state on the halflives of occupational exposure indicators. The percentages relate the biological levels at apparent steady state to steady state levels calculated using Equation (12). The calculation describes conventional work cycles of five 8 h shifts per week. The intercepts on the abscissa indicate the longest half-lives which allow the apparent steady state to be reached during the first working week. level. Since the reference values for biological monitoring (such as BE1 and BAT) are meant for steady state conditions, biological specimens should be collected after a `waiting period'. The waiting period for exposure indicators with different halflives can be estimated from the bold line in Fig. 2 (indicated by go%), or calculated using Equation (13). Fig. 2 can also be used to estimate what fraction of the steady state value represents the measurement taken after a known length of employment. For practical purposes, it is satisfactory if the reference values are compared with measurements in samples collected as follows: (a) ti12 < 45 h: sampling after 1 week of exposure. Day in the working week and timing in relation to the beginning and the end of exposure are critical. (b) t l i 2 < 9 days: sampling after 1 month of employment. At steady state, timing I I 350 V. Fiserova-Bergerovaand J. Vlach Table 1, Constants q for Equation ( I 3) Levels, -~ ~~~ 99.99Yo 99.9% 99.0% 90.0% 75.0% 50.0% 9 1.110 1.228 I .40i I .665 1.921 2.165 11/2t 13 h 17h 25 h 45 h 83 h 166h `Biological levels at apparent steady state expressed as percentage of biological level at real steady state.fLongest half-lives which allow reaching of apparent steady state during the first work week.They equal antilogarithms of q. (See x-intercepts in Fig. 2.) (c) tl12 < 3 months: sampling after 1 year of employment. Timing with respect to the shift and working week is unimportant. (d) ri!2 > 3 months: sampling should be repeated each 6 months. A rise in the biological level and possible exceeding of the reference value should be observed. For example, the elimination of cadmium in urine ( t l l z = 12 h, 2.7 days, and I O years), is triphasic. The shortest half-lives, which control the rapid rise of biological levels at the beginning of employment, indicate that sampling after 1 week of employment is appropriate. The long half-lives, however, indicate that regular yearly control is necessary. Fig. 2 indicates that measurements taken after around 30 weeks of employment represent about 50% of the lifetime employment level, and that measurements taken after 1 year of employment represent about 75% of the lifetime employment level. Half-lives of lead in blood 1.3 month, 6 months, and 40 years) indicate that the steady state would be reached after 70 years of employment. This means that the lead levels in blood rise over the whole working life, making periodical checkups advisable. However, half-lives of indicators of exposure to organic solvents are shorter than 3 days. This means that the apparent steady state is reached within a month of employment, but sampling time with respect to the week day is critical. The recommended sampling times of biological specimens based on the half-life of the exposure indicators are shown in the last column of Table 2. Conclusions Special attention should be given to the sampling time of biological specimens for measurements of exposure indicators. For indicators with a short half-life, the timing is crucial with respect to the day in the working week and to the beginning and end of the shift in which exposure occurs. Recommended sampling times for reference values should be followed strictly. For agents with a long half-life, the timing of `sampling is crucial with respect to the duration of employment (not with respect to the work shift). A regular yearly check-up is indicated. The reference values (BEI, BAT) for slowly eliminated exposure indicators indicate that timing is `not critical' (BEI), is `discretionary' (BEI), or that sampling `after several shifts' (BAT), is recommended. It would be more appropriate if the reference values k 1 t t , ACETONE Acetone, ur. ANILINE p-arninophenol ARSENIC Inorganic As, ur. BENZENE phenol. ur. benzene, air CADMIUM Cd,ur. Cd,bl. CARBON DISULFIDE TTCA, UT. CARBON MONOXIDE CO-Hb, bl. CO, air CHLOROBENZENE 4-chlorocatechol, ur. p-chlorophenol, ur. CHROMIUM (VI) Cr, UT. COBALT Co, ur. Co,bl. N,N-DIMETHYLACETAMIDE N-Methylacetarnide, ur. N,N-DIMETHYLFORMAMIDE N-methylformarnide, ur. 2-ETHOXYETHANOL 2-ethoxyacetic ac., ur. ETHYLBENZENE Mandelic acid, ur. FLUORIDES FL,UT. FURFURAL furoic acid, ur. n-HEXANE 2,5-hexanedione, ur. LEAD Pb, bl. MERCURY inorg. Hg, ur. inorg. Hg, bl METHANOL methanol, ur. METHYLCH LOROFORM methylchloroform. air TCAA, ur. TCE, ur. TCE, bl. METHYL ETHYL KETONE MEK, ur. METHYL ISOBUTYL KETONE MIBK, ur. NITROBENZENE p-nitrophenol, ur. Es Es EW Es PS NC NC Es Es Es ES Es ES,EW ES, EW ES, EW ES, EW ES ES, EW ES, EW Es Es ES NC PS ES, EW ES PS, EW EW ES, EW ES, EW Es ES ES, EW 3.5 3, 10 6 0.4, 2.5 12 I, 3.5, 8 1.2 I .25 2.1 2 5 5 2.2 3 7 12 3, 7 5 4-7 2 14 2 1.5 I1 I1 .5, 1.35 .7, 7 8 ')* .72 .5 15-30 42 2.7, 59 .67 I .9 1 40 40 10, 28 1.3 3 352 V. Fiserova-Bergerova and J. Vlach Table 2-continued Notation Half-lives of BEIs Hours Days Years Recommend. PARATHION p-nitrophenol, ur. PENTACHLOROPHENOL PCP, ur. PCP, PI. PERCHLOROETHYLENE perchloroethylene, air perchloroethylene, bl. TCAA, ur. PHENOL phenol, ur. STYRENE mandelic acid, ur. phenylglyoxylic ac., ur. styrene, bl. TOLUENE hippuric acid, ur. toluene, bl TRlCHLOROETHYLENE TCAA, ur. TCAA + TCE, ur. TCE, bl. VANADIUM PENTOXIDE V, ur. XYLENES methylhippuric ac., ur. ES PS, EW ES PS, EW PS, EW EW ES ES PS Es PS Es PS Es Es EW ES, EW ES, EW ES, EW ES 8 28, 4.3 .25, 4 3.5 3.5 8 .6, 13 I .2 1.2, > 30 3.1 4 3.3 1.4 2 .5, 3.1 12 3.6 3.2 3 .8 1.25 .2 ES, EW a C C PS, EW b PS, EW b ES, EW b ES a ES, EW a PS, EW a ES, EW a PS, EW a ES, EW a PS, EW a ESa ES, EW b ES, EW b ES, EW b ES, EW a ES, EW a ES, EW a Notation indicates sampling time for BEIs: Es = end-of-shift; PS = prior-to shift; EW = end-of- week;NC = not critical or discretionary. ur. = urine sample; bl. = blood sample; air = exhaled air sample. Recommendation is based on the half-life analysis in this paper. a-d, which relates to cumulation over the long-term employment, are explained in text. EW is based un the half-life of the BE1 as shown in the Appendix. Half-lives as cited in BE1 documentation (American Conference of Governmental Industrial Hygienists, 1991). * There are indications of cumulation of 2-thiothiazolodine-4-carboxylicacid. The half-life of the slow phase, however, is not determined. EW notation is used as a precaution. defined the `waiting period', and discouraged sampling shortly after a worker had returned to work from a vacation or other long absence. REFERENCES American Conference of Governmental Industrial Hygienists (1991) Documenfurionofthe Threshold Limif Vulues and Biological Exposure Indices, Sixth Edition. Cincinnati, OH. Deutsche Forschungsgemeinschaft: List of MAK and BAT Values 1995, Report No. 31. VCH Verlagsgesellfschaft, Weinheim. APPENDIX Es indicates that sampling at the end of the shift is required for agents with a half-life shorter than 4 days. This criterion is based on the assumption that the