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James Etal2008
James Etal2008
James Etal2008
James Etal2008
James Etal2008
James Etal2008
James Etal2008
James Etal2008
James Etal2008
James Etal2008
James Etal2008
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James Etal2008


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Worker Exposure
to Secondhand Smoke
Evaluating a prediction model
By Harry R. James, Lisa Barfield, Janice K. Britt and Robert C. James
OCCUPATIONAL EXPOSURE to secondhand smoke
(SHS)—also known as environmental tobacco
smoke—still occurs. According to the U.S. Surgeon
General, “Approximately 30% of indoor workers in
the U.S. are not covered by smoke-free workplace
policies” (DHHS, 2006). Occupational safety professionals
and agencies have investigated SHS exposures
to workers in the hospitality industries (e.g., restaurants,
lounges, casinos), as well as in offices or environmentswhere
smokingwas allowed (Trout, Decker,
Mueller, et al., 1998; Repace & Homer, 2005; Repace,
Hughes & Benowitz, 2006b).
For example, professionals investigating indoor
air quality (IAQ) complaints have long known that
one must rule out the possible contribution of smoking
to the environmental and health impacts being
evaluated (Hodgson, 1989). Given the potentialmagnitude
and concern for SHS in occupational environments
(DHHS, 2006; CDC, 2007; Goodwin, 2007;
WHO, 2007), SH&E professionals must continue to
characterize SHS exposure levels in the workplace.

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  • 1. OccupationalHazards Occupational Hazards Worker Exposure to Secondhand Smoke Evaluating a prediction model By Harry R. James, Lisa Barfield, Janice K. Britt and Robert C. James O OCCUPATIONAL EXPOSURE to secondhand smoke (SHS)—also known as environmental tobacco smoke—still occurs. According to the U.S. Surgeon General, “Approximately 30% of indoor workers in the U.S. are not covered by smoke-free workplace [This is particularly true given the fact that legal actions have been initiated by nonsmoking employ- ees against companies that fail to consider SHS expo- sures (e.g., see primer on legal actions against Casinos found at policies” (DHHS, 2006). Occupational safety profes- documents/casino.pdf). In fact, it is believed that sionals and agencies have investigated SHS exposures such litigation will only increase (Sweda, 2001)]. to workers in the hospitality industries (e.g., restau- It is also conceivable that biomonitoring of rants, lounges, casinos), as well as in offices or envi- employees could mitigate claims of respiratory ronments where smoking was allowed (Trout, Decker, injuries or cancers against employers if it were deter- Mueller, et al., 1998; Repace & Homer, 2005; Repace, mined that the worker’s personal smoking habit— Hughes & Benowitz, 2006b). off the job, and not the worksite—was a more likely For example, professionals investigating indoor causal factor. The monitoring of tobacco smoke may air quality (IAQ) complaints have long known that also be of interest to SH&E professionals when one must rule out the possible contribution of smok- chemicals in SHS are routinely being monitored for ing to the environmental and health impacts being in the workplace (e.g., carbon monoxide). evaluated (Hodgson, 1989). Given the potential mag- For the SH&E professional, quantitation of work- nitude and concern for SHS in occupational environ- er exposure to SHS is a logical step toward under- ments (DHHS, 2006; CDC, 2007; Goodwin, 2007; standing the scope and depth of this issue. WHO, 2007), SH&E professionals must continue to One potential tool for exposure assessment that characterize SHS exposure levels in the workplace. could overcome the potential limitations of area or personal monitoring is biomonitoring. Biological Harry R. James is chief indoor air quality (IAQ) and industrial hygiene field monitoring, when using a validated methodology investigator for TERRA Inc., a toxicology consulting firm in Tallahassee, FL. He performs (Lauwerys & Hoet, 2001; Sexton, Callahan & Bryan, investigations, monitors workers, writes site safety plans and manages remediation of 1995), moves the measurement from the potential of workplaces suspected of having IAQ problems and performs Phase I and II site exposure (the opportunity for interaction between assessments. He holds a B.A. from the University of Utah and is pursuing a master’s the worker and the chemical) to a more direct meas- degree in occupational safety and health from Columbia Southern University. ure of dose (the specific quantity of the chemical Lisa Barfield, M.S., is a toxicologist with TERRA Inc. She holds an M.S. in absorbed systemically by the worker). This not only Interdisciplinary Toxicology from University of Arkansas for Medical Sciences. Barfield individualizes each worker’s exposure, it also elimi- has 17 years’ experience in toxicological and environmental services, including nates the question of whether area monitoring is suf- toxicology, human health risk assessment, environmental regulatory analysis, product ficient to capture each worker’s exposure. For SHS stewardship, human health hazard assessment and product liability. exposures, biomonitoring is performed via serum or urinary nicotine metabolite (cotinine) measure- Janice K. Britt, Ph.D., is a toxicologist with and vice president of TERRA Inc. She has ments. (See for example ACGIH’s Introduction to more than 15 years’ experience in the field of toxicology. Britt holds a B.S. in Zoology the Biological Exposure Indices at and a Ph.D. in Toxicology from Texas A&M University. Her primary focus at TERRA is on products/beiintro.htm.) the human health impacts of various chemicals as well as conducting risk assessments. Furthermore, biomonitoring for specific, exposed Robert C. James, Ph.D., is a toxicologist with TERRA Inc. and an associate scientist with employees might well reduce expenditures when the Center for Environmental and Human Toxicology at the University of Florida, where compared to wholesale monitoring of an entire site. he conducts research and teaches graduate-level courses in toxicology and risk assess- Thus, the utility of determining SHS exposure ment. James holds a B.S. in Chemistry and a Ph.D. in Pharmacology from the University through a simple, cost-efficient biomonitoring proto- of Utah. He is a chief author and editor of Principles of Toxicology: Environmental and col via urinalysis should be attractive to practitioners. Industrial Applications (2nd ed.) and is a member of the Society of Toxicology, the Short of an enforced smoking ban in all places of Society of Environmental Toxicology and Chemistry, and the Society of Risk Analysis. business (and all places a worker is expected to be as 34 PROFESSIONAL SAFETY SEPTEMBER 2008
  • 2. a function of his/her job), how can one determine the Given this endorsement, SH&E professionals per- relative safety of the working population as it relates forming assessments of workforce SHS exposure to SHS? How does an epidemiologist or public health might employ these equations, believing they pro- official quantify exposure in a free-ranging population vide reliable estimates of discrete SHS exposure for to determine the relative contribution of SHS to health specific individuals. However, Repace, Al-Delaimey impacts? Not all people work in specific, controlled et al. (2006) concede that these equations tend to bet- environments. For example, installers, repair person- ter predict group mean or median values and that Abstract: SH&E profes- nel and contractors may visit homes and private busi- they are less accurate for individual values as one sionals may be asked to nesses where smoking is allowed; thus, they might not moves away from the central tendency value of the determine secondhand be ideal subjects for traditional industrial hygiene distribution (Repace, Jinot, Bayard, et al., 1998). smoke (SHS) exposures evaluation and control methodologies. Mobile em- Therefore, the purpose of this article is to perform as a part of worker ployees or those who work outdoors and outside a simple validation assessment of the model and its safety or exposure direct management control might themselves smoke, reported predictive utility. This was achieved by assessments. This article which could skew exposure data. employing a NIOSH study dataset that contains critically examines a A benefit to having a noninvasive biological mon- contemporaneous measurements of most end- recently proposed set itoring program that would readily identify exposure points/outputs of the model’s equations. Thus, the of equations for pre- patterns to SHS would be the evaluation of ventila- NIOSH study provides the kind of data that would dicting concentrations tion systems in various settings. If nicotine and res- be useful for determining how reliably one can of SHS markers in air. It pirable suspended particles (RSP) concentrations extrapolate or predict SHS exposure that resulted in concludes that such were to be accurately predicted by cotinine in urine, the biomonitoring measurement one has taken. models should not be the engineer responsible for ventilation would have employed until they excellent data on the efficacy of his/her work with- The NIOSH Data Used for Validation are fully validated and out going through the expense of personal and area NIOSH conducted a health hazard evaluation asserts that use of monitoring. Job safety assessment would be (HHE) of a group of nonsmoking employees of measured, population- enhanced with such exposure data as well. Worker Bally’s Park Place Casino Hotel in Atlantic City, NJ specific, SHS concentra- health programs could be tailored to monitor for (Trout & Decker, 1996; Trout, et al., 1998—hereafter tions should remain the those health effects seen in overexposed populations, referred to as the NIOSH casino study). In this study, preferred practice in and ruling out SHS contribution to the total environ- samples were collected during a 2-day exposure job safety assessment mental load of a worker’s exposure to other contam- interval. These included area respirable particulate for this potential work- inants would allow professionals to concentrate on monitoring, area and personal monitoring of air place hazard. other likely sources of exposure (e.g., PAHs, amines, nicotine, and biological measurements of environ- aldehydes, RSP and other chemicals that come from mental tobacco smoke (ETS) exposures consisting of SHS) (DHHS, 2006). Currently, there is no biological both pre- and postshift serum and urine cotinine lev- monitoring standard for SHS exposure. els. (The casino workers also answered a question- A recent publication by Repace, Al-Delaimy and naire that provided information on their estimated Bernert (2006) presents a series of simple equations duration of exposure to ETS while at home and at that the authors refer to as the Rosetta Stone calcula- work on the day that samples were taken, and for tions (hereafter referred to as the the 3 days before samples model or the model’s equations). were collected.) These authors suggest that a reli- Cotinine This NIOSH dataset is the able mathematical relationship Cotinine is a metabolite formed by type of SHS exposure sce- for predicting certain atmospher- the body from nicotine, which is a nario an SH&E professional ic markers of SHS from single chemical in tobacco smoke and could be faced with in a non- cotinine biomonitoring measure- chewing tobacco. Levels of cotinine industrial setting. Repace, Al- ment now exists. Assuming these in blood indicate the amount of Delaimy, et al. (2006) suggest equations could be shown as reli- exposure a person has had to that by using their model one ably predictive, the equations tobacco smoke. A laboratory test can reliably move between might be an effective tool for can measure cotinine in blood, urine air measurements of SHS screening or determining the or saliva. exposure and biomonitoring magnitude of worker exposure to measurements that reflect the SHS, especially the urinary and Cotinine Exposure nicotine levels associated saliva cotinine as they are nonin- Nicotine gets into people’s bodies with that exposure. Physical vasive measurements. Repace, if they: and pharmacokinetic (PK) Al-Delaimy, et al. state that using •Smoke or chew tobacco. All models are given that enable these equations, different markers people who smoke have cotinine in intercomparison of studies of for SHS exposure can be reason- their bodies. SHS exposure using atmos- ably estimated if just one surro- •Are exposed to secondhand pheric markers (CO, RSP and gate marker is measured, and that tobacco smoke (also called environ- nicotine) and biomarkers these equations then permit mental tobacco smoke). (serum saliva, urine cotinine “intercomparison of clinical and •Are involved in tobacco produc- and hair nicotine). According atmospheric studies of SHS for tion and handle tobacco. to Repace, Al-Delaimy, et al., the first time.” the dataset in the NIOSH SEPTEMBER 2008 PROFESSIONAL SAFETY 35
  • 3. Table 1 Table 1 NIOSH Casino Study, Individual Measurements nicotine) and personal air (nico- tine only) monitoring samples were conducted for approxi- mately 8 hours during each workshift, and the reported air concentration results were expressed as 8-hour time- weighted averages (TWAs). Subject #8 was considered an active smoker (due to high preshift urine and serum coti- nine concentrations) and was subsequently eliminated from analyses by the study authors and from the present analysis. NIOSH staff statistically compared pre- and postshift serum cotinine levels in the remaining 28 participants who reported SHS exposure outside of their work to those who reported no SHS exposure out- side of work (Trout, et al., 1998). No statistically significant dif- ference was observed, indicat- ing that the cotinine levels measured in these individuals were not significantly influ- enced by nonwork SHS expo- sures. There also were no statistically significant differ- ences in measurements between the two shifts (Trout & Decker, 1996), allowing an analysis to be conducted using combined data from both shifts. Table 1 pro- vides a summary of the NIOSH casino study’s individual work- er nicotine/cotinine data. Table 2 lists data from area nicotine and RSP air monitoring. Results indicated air nicotine concentra- tions from personal monitors (4 to 15 µg/m3) and area monitors (6 to 16 µg/m3) to be compara- ble across their ranges. Application of the Model’s Equations casino study, which collected both SHS exposure to the NIOSH Study Data measures and biomonitoring samples from a single Repace, Al-Delaimy, et al. (2006) proposed the fol- workplace, should provide a means to evaluate the lowing equation to model the relationship between reliability of the model’s equations because all of urine cotinine and air nicotine: these measurements were taken contemporaneously aU = Kϕαρδ HN/δ V [Equation 1] and need no qualification. One should be able to cal- r t u culate the model’s equations forwards or backwards Where: to determine their predictive utility using this dataset. U = cotinine in urine, ng/mL Twenty-nine nonsmoking casino employees partic- K = conversion factor of 1,000 ng/µg ipated in the study. They were working one of two ϕ = nicotine to cotinine conversion efficiency by 8-hour shifts. Participants provided pre- and postshift liver enzymes, 0.78 (unitless) urine samples; 28 of 29 also provided pre- and post- α = nicotine absorption efficiency, 0.71 (unitless) shift serum samples for cotinine analysis. The urine ρ = typical adult respiration rate for light activity, cotinine concentrations were total cotinine (free coti- 1 m3/hour nine plus cotinine glucuronide). Area air (RSP and δr = renal cotinine clearance rate, 5.9 mL/min 36 PROFESSIONAL SAFETY SEPTEMBER 2008
  • 4. δt = total cotinine clearance rate, 64 mL/min plus cotinine that is conjugated with glucuronide. In Vu = adult daily urine output, 1,300 mL/day Repace and Homer, the method for converting urine H = hours exposure total cotinine to urine free cotinine is to divide urine N = air nicotine concentration, µg/m3 cotinine by 1.5 (effectively multiplying total cotinine aFrom equation 4, p. 182 and Table 1, p. 184 of concentrations by 0.67 to yield the free cotinine lev- Repace, Al-Delaimy, et al. (2006). els). As noted, in the unpublished report (Repace), urine total cotinine concentrations were multiplied Solving for N from measured urine cotinine, the equation is as follows: N = U* δt Vu/KϕαρδrH [Equation 2] Table2 2 Table Using the default pharmacokinetic parameters and adult respiration rate for light activity, the equa- NIOSH Casino Study, tion becomes: N = U*25.46/H [Equation 3] Area Measurements They then presented equations that encompassed the above-modeled relationship between urine coti- nine and air nicotine, as well as the relationship between air nicotine and other markers of SHS in air. The equations that are applicable to adult exposures are shown in Table 3. For some conversion equations (e.g., carbon monoxide, polycyclic aromatic hydro- carbons, salivary cotinine), there is no corresponding measured data in the NIOSH casino study, so these equations could not be evaluated. The remaining applicable set of equations evaluated was: RSP from air nicotine (Equation 4), serum cotinine from urine cotinine (Equation 5), and air nicotine from plasma (serum) cotinine (Equation 6). Estimating Urine Free Cotinine Concentrations From Urine Total Cotinine Concentrations It was unclear whether Repace, Al-Delaimy, et al. (2006) used total or free urine cotinine as the input value, and whether cotinine present in preshift sam- ples was to be subtracted from postshift samples. This is noted because an unpublished study of casino workers (Repace, 2006) that initiated this compara- tive analysis estimated free urinary cotinine levels from the measured total cotinine using a 0.508 con- version factor. Thus, it was surprising that the article describing the model did not mention the need to use free or total cotinine values when estimating air nico- tine concentrations from urinary cotinine measure- ments. Moreover, in two other recent SHS studies by the model’s authors (Repace & Homer, 2005; Repace, Hughes, et al., 2006) Table3 3 Table the equations were applied to estimate SHS exposures in nonsmoking individuals Rosetta Stone Conversion Equations from urine cotinine. However, in all three studies, different, additional procedures for Adult SHS Exposure for applying the model’s equations are revealed that are not presented in the Repace, Al-Delaimy, et al. publication. These additional procedures include: 1) The conversion of urine total coti- nine to free cotinine must be made, appar- ently because the equations were derived based on free cotinine (Repace & Homer, 2005; Repace, 2006). Total cotinine meas- ured in urine is the sum of “free” cotinine SEPTEMBER 2008 PROFESSIONAL SAFETY 37
  • 5. Table4 4 Table Conversion of NIOSH Casino Study Urine Total Cotinine to Urine Free Cotinine, Methods A & B average air nicotine concentration cannot be accurately calculated from a single, postshift urinary cotinine measurement. 3) In Repace and Homer (2005), subjects were instructed to avoid SHS as much as possible for 5 days before their exposure in the bar. In Repace (2006), subjects had worked several days before their exam- ined shift exposure and were, therefore, more similar to the postshift exposure pat- tern seen in the NIOSH casino study. 4) Repace, Hughes, et al. (2006) was a study similar to that of Repace and Homer (2005), in which urine cotinine was meas- ured in 8 volunteers before a 6-hour visit to an area bar, followed by two postvisit sam- ples at 2 and 12 hours. To obtain the urine cotinine concentration used to estimate exposure to SHS-RSP, background (e.g., preshift) cotinine was subtracted from the postshift concentrations and the two back- ground-corrected postshift samples were then averaged. Repace, Hughes, et al. (2006) did not discuss the issue of free ver- sus total urinary cotinine in that study, and the method the study authors cited describ- ing the urine sample analysis (Bernert, Turner, Pirkle, et al., 1997) appears to be a serum cotinine method. These disparate methods are referred to as Method A (based on Repace & Homer, 2005) and Method B (based on Repace, 2006). In Method A, urine free cotinine is calculated by dividing total urine cotinine by 1.5, and the equations are run on the difference between pre- and postshift coti- nine concentrations. In Method B, urine free cotinine is calculated by multiplying total urine cotinine by 0.508, and applica- ble equations are applied to the postshift concentrations. These two methodologies were then applied to the NIOSH casino study urine cotinine measurements to esti- mate the concentration of urine free coti- nine to be used in subsequent calculations. by 0.508 to calculate urine free cotinine levels. This The estimates produced by both Method A single difference in the application of just one of the and Method B are shown in Table 4. model’s equations can alter the final RSP/nicotine The concentrations derived using Method A and calculations by 24 to 32%, depending on the correc- Method B differ considerably. Method A is a deter- tion factor employed. mination on the net change of cotinine from pre- and 2) Repace and Homer (2005) took one preshift and postshift—that is, contribution from preshift expo- two postshift samples (at 2 and 9 hours postexpo- sure is subtracted out. Method B does not include a sure). The two postshift samples were averaged, correction for contributions from preshift exposure, preshift concentrations were subtracted from the even though this should occur for individuals with postshift averages, and the calculations were applied known exposures from shifts from previous days. If to the net difference. In contrast, in Repace (2006) this correction is not made, the air nicotine and RSP only postshift urine samples were taken for cotinine calculated is greater than that from any one shift analysis, so the equations were applied to the uncor- because not all cotinine derived from metabolism is rected postshift urine cotinine measurement. The cleared in 1 day. Thus, postshift serum and urinary timing of the postshift sample collection varied from concentrations in workers should typically increase about 6.5 to 23 hours after the shift end. Thus, the for each day of exposure during the week before the Repace and Homer report shows why a worker’s measurement is taken. 38 PROFESSIONAL SAFETY SEPTEMBER 2008
  • 6. Three of the NIOSH casino study subjects had measurements in the subset consisting of the 17 preshift urine concentrations that were higher than NIOSH casino study workers for which such monitor- postshift concentrations. This is likely because of ing was performed (Table 6, p. 40). Based on the arith- some preshift exposure to SHS that was higher than metic averages, the model’s equations, when using the exposure during the examined shift. Taking both Method A, overestimated air nicotine concentrations differences in the methods into consideration, by about 2 to 3-fold. When using Method B, the over- Method B results, on average, in much higher urine estimate was approximately 6 to 7-fold. For subjects cotinine concentrations when multiple exposures with air monitoring data, all air nicotine estimates were have occurred, and so, higher estimated SHS expo- exaggerated regardless of the calculation method used. sure levels than Method A. By dividing total cotinine In addition, as no method for converting “total” by 1.5 in Method A, the average estimated free coti- cotinine to “free” cotinine is described in Repace, Al- nine for a given total cotinine concentration is Delaimy, et al. (2006), anyone relying solely upon the approximately 1.3 times greater than the free coti- model will generate even higher overestimations nine estimation for Method B (multi- plying by 0.508). Table 5 Table 5 Estimating Air Estimating NIOSH Casino Study Air Nicotine Nicotine Concentrations Concentrations From Urine Free Cotinine Levels The model sug- gests that air nico- tine concentration (in units of µg/m3) can be estimated from urine free coti- nine (ng/mL) using Equations 1, 2 and 3. Equation 3 was ap- plied to the NIOSH study urine free coti- nine estimated by both Methods A and B. For Method A, air nicotine estimates were only derived for those subjects with an increase in urine cotinine pre- to postshift; those with a negative change in urine cotinine were excluded from the estimate. The results are shown in Table 5. The mean estimated air nicotine from Method A urine free cotinine was 26.2 µg/m3 (8-hour TWA) and from Method B urine free cotinine was 67 µg/m3 (8 hour TWA). The predictive accuracy of model Equation 3 was test- ed by comparing estimated nicotine concentrations to personal monitor SEPTEMBER 2008 PROFESSIONAL SAFETY 39
  • 7. Table6 6 Table Personal Monitor Nicotine Concentrations Compared to Estimated Concentrations From Urine Cotinine The results of this compara- tive analysis are shown in Table 7. The predictive ability of this equation was then examined by comparing esti- mated RSP concentrations to the area RSP measurements (Table 8, p. 42). This compari- son indicates that mean RSP estimated from air nicotine, which was in turn estimated from urine free cotinine levels, was 4.71 times greater using Method A and 12 times greater using Method B than the reported, measured mean for area RSP. The mean estimated RSP derived using measured nicotine concentrations via per- sonal monitors was 1.72 times greater than the measured RSP. As occurred with the com- parisons between estimated and measured air nicotine, using the model’s equations to estimate personal or area RSP exposures for SHS from the workers’ free urine cotinine measurements (using either Method A or B) results in a significant overesti- mate of SHS exposure. The more levels of estimation involved (RSP estimation from urine cotinine versus RSP esti- mation from air nicotine), the greater the degree of SHS over- estimation. All group and aver- age measurements, and almost every individual measurement, were exaggerated when the should they inadvertently apply these equations to a model’s equations were used to predict them. For total cotinine measurement. This comparison indi- example, the maximum estimated RSP exposure for a cates that the equations cannot be used to reliably NIOSH casino study subject (from Method B urine estimate air nicotine exposures from urine cotinine free cotinine) was 3,185 µg/m3, which is 35 times the concentrations, either for a group or for a particular maximum measured value of area RSP (90 µg/m3). individual. Application of this model to urine coti- The lowest estimated RSP exposure for a NIOSH casi- nine measurements tends to result in a significant no study subject was 63 µg/m3, greater than 3 times overestimate of worker SHS exposure. the lowest measured air RSP concentration reported in the NIOSH casino study (< 20 µg/m3). Estimating Air Nicotine Concentrations The range of urine total cotinine measurements in From RSP Concentrations the NIOSH casino study subjects varied about 40 fold The model provides the following equation for (range: 3.87 to 197 ng/mL) from exposures that varied estimating RSP in air from air nicotine: only about 2-fold for nicotine air concentrations and RSP = 10x (nicotine concentration in air) only about 3-fold for air RSP concentrations. Thus, [Equation 4] (Ux25.46/8x10) individual worker variations in the inhalation, absorp- RSP concentrations were estimated using: tion and metabolism of the respective room air nicotine 1) The estimated nicotine concentrations from the concentrations, when extrapolated on an individual NIOSH casino study based on estimated urine free basis, suggested a greater variation in room air nicotine cotinine measurements (Methods A and B); and RSP concentrations than actually existed. 2) The measured area nicotine concentrations in This variation is important as the implied purpose the NIOSH casino study to derive an estimated RSP of the model’s equations is to obviate the need to take concentration. serum nicotine/cotinine and air nicotine and RSP 40 PROFESSIONAL SAFETY SEPTEMBER 2008
  • 8. measurements by simply taking a worker urine sam- Where: ple and measuring its cotinine level. However, to do inhalation rate = assumed 1 m3/hour; so will increase the variation in the estimates of SHS exposure duration = for this analysis, assumed exposure, substantially increase the maximal estimate 8-hour work shift. and, thereby, increase even the average estimate of Although not stated clearly in Repace, Al-Delaimy, exposure. In short, there is an obvious potential for the et al. (2006), this equation should be applied to the dif- SH&E professional or epidemiologist to overestimate ference between a pre- and postshift serum concentra- an individual’s SHS exposure substantially when one tion for the most accurate results. This equation was, simply applies the model’s equations to urine cotinine therefore, applied to the NIOSH casino study postshift measurements, for either the individual or the group. serum cotinine concentrations, both estimated and measured, to predict air nicotine concentrations. These Serum Cotinine Concentrations estimated concentrations were then compared to the Estimated From Measured Urine Cotinine measured nicotine concentrations taken from personal Concentrations air monitoring samples from the NIOSH casino study. The ability of the model to predict or estimate the serum cotinine concentrations from Table 7 Table 7 one’s urine cotinine concentra- tions [Equation 5: serum coti- Estimation of RSP Concentrations nine = urine free cotinine/6.5] was examined using the NIOSH From Estimated Nicotine Concentrations casino study data. This equation was applied to preshift and postshift urine free cotinine con- centrations as estimated by Method B (urine total cotinine x 0.508 = urine free cotinine). Based on group averages, Equation 5, when applied to urine free cotinine derived by Method B, overestimates meas- ured serum cotinine by about 1.5- to 1.6-fold. A review of indi- vidual preshift measurements indicated that serum cotinine was overestimated in 18 of 27 individuals; postshift measure- ments indicated serum cotinine was overestimated more fre- quently (24 of 27 individuals), and sometimes by more than 5- fold. This procedure also does not allow one to consider the possibility that the last exposure interval serum cotinine concen- trations might have been lower than prior exposure intervals, which in fact occurred in 5 sub- jects in the NIOSH casino study (subjects 1, 4, 13, 14 and 17). Estimating Air Nicotine Concentrations From Serum Cotinine The following equation de- scribes the relationship be- tween serum cotinine and air nicotine concentrations: (serum cotinine) = 0.006 x (inhalation rate) x (exposure duration) x (air nicotine con- centration) [Equation 6] SEPTEMBER 2008 PROFESSIONAL SAFETY 41
  • 9. Table8 8 Table Comparing the Average Estimated RSP Concentrations to the Average Measured Area Monitoring Results From the NIOSH Casino Study The results of these comparisons show that the Conclusion estimated air nicotine concentrations derived using Whether SHS can be determined to be a health the model’s equations predicted concentrations hazard, either by itself or as a contributor to total higher than those actually measured by NIOSH particulate or chemical exposure, worker exposure investigators. A comparative analysis (data not to it will be laid at the feet of the professional who shown but available upon request), indicated that makes no effort to characterize these exposures and measured nicotine concentrations from personal address them accordingly. Worker exposure to car- monitoring samples averaged 4.1-fold lower than cinogenic or debilitating agents can generally be those estimated via the corresponding model equa- effectively monitored through personal or area tions. The overestimation was compounded when measurements of the offending agent. the model’s air nicotine concentration was derived This is the basis for deriving and setting safe from an estimated serum concentration that in turn workplace exposure values such as threshold limit was derived from a urinary free cotinine concentra- values as controls for chemical exposures. Some bio- tion. Air nicotine levels estimated in this manner logical monitoring of chemical metabolites has also averaged 7-fold higher than measured values (com- been accepted as a tool for ensuring that overexpo- parison not shown but available upon request). sure does not occur (e.g., benzene exposure via phe- nol in urine and blood lead measurements). Control Calculating Serum & Urinary Cotinine of exposures deemed excessive by comparison to the Concentrations From Measured Air Nicotine recommended exposure guideline can then proceed Concentrations using traditional safety engineering principles. As a final examination of the model’s predictive In the present analysis, several compounds or utility, the equations were used to reverse-calculate metabolites collected while monitoring workers individual serum and urine cotinine concentrations exposed to SHS were evaluated by comparing these from personal nicotine air measurements taken in measured values to predicted values for each expo- the NIOSH casino study. Equation 3 was used to sure marker generated using a model proposed by estimate the urinary cotinine concentration from the Repace, Al-Delaimy, et al. (2006). measured air nicotine concentration, and Equation 6, The comparative analyses, using contemporane- once rearranged, was used to estimate the serum ous data generated by NIOSH of all the model’s sug- cotinine concentration from the measured air nico- gested surrogate marker compounds, revealed that tine concentration. These estimated values were this model (or more precisely, this collection of sim- then compared to the measured concentrations ple, algebraic equations) cannot be used to accurate- (again these results are not shown in the interest of ly estimate one surrogate marker of SHS exposure space but can be made available upon request). from the measurement of another surrogate marker Based on group averages, estimating a serum of SHS exposure. cotinine concentration from an air nicotine measure- In fact, the comparative analysis indicated that the ment resulted in a 4.4-fold underestimate of the NIOSH casino study data could not be reasonably serum cotinine. Estimating a urine cotinine concen- predicted by the model’s equations to any acceptable tration from an air nicotine measurement results in degree of accuracy—neither for individual measure- an 8-fold underestimate. Just as the model’s equa- ments nor for the statistical characterizations of tions overestimate air concentrations of nicotine and group exposures (e.g., mean values). Because of these RSP from urine and serum cotinine measurements, inaccuracies, which occur if one moves from a bio- the equations conversely underestimate urine and marker chemical measured in a worker’s serum or serum cotinine concentrations when using a meas- urine to airborne concentrations of chemicals or vice ured nicotine air concentration. versa, the authors strongly recommend that this 42 PROFESSIONAL SAFETY SEPTEMBER 2008
  • 10. model or set of equations not be used in either the nicotine to cotinine and the processes for eliminating workplace or in public health studies. cotinine from the blood compartment. As written, the model’s equations tend to underes- As an example of this, comparative analyses using timate the serum and urinary concentrations of coti- the NIOSH casino study data showed that measured nine that an individual generates when s/he RSP and nicotine exposure levels which varied no metabolizes inhaled nicotine, and correspondingly more than 3-fold for the group, resulted in a greater exaggerate inhaled nicotine and RSP levels when than 40-fold variation in the magnitude of group uri- based on an individual’s or group’s serum/urinary nary cotinine concentrations. No simple algebraic cotinine measurements. The perceived utility of this equation, which always multiplies a single constant model’s equations is indirect measure- ment of SHS (i.e., Table 9 Table 9 to use the noninva- sive urinary cotinine Comparing Measured NIOSH Casino Study measurement to pre- dict SHS inhalation Serum Cotinine Levels to Serum Cotinine Levels exposure). However, use of Estimated From Urine Free Cotinine (Method B) this model by SH&E personnel in the workplace will only overstate SHS expo- sure to a substantial degree. Thus, safety assessment is best performed by a direct measurement of accepted SHS markers. The reason for the inaccuracy of the model’s equations rests largely in the fact that there is con- siderable interindi- vidual variation in the metabolism of nicotine to cotinine. Available data (Ben- owitz, 1996; Huk- kanen, Jacobs & Benowitz, 2005) on the metabolism of nicotine indicates that this variation is too great to be able to convert cotinine to air nicotine levels with a single conver- sion factor as the model’s equations attempt to do. Thus, the sugges- tion that a single, linear relationship exists is incorrect and is an oversimplifica- tion of the biologic processes involved in the absorption of nicotine, the bio- transformation of SEPTEMBER 2008 PROFESSIONAL SAFETY 43
  • 11. value by the measured concentration of one surro- predictions for more traditional industrial hygiene gate marker of SHS exposure that has been meas- air monitoring methods for use in an exposure ured, can capture this 40-fold variation. Thus, one assessment. The poor predictive ability demonstrat- cannot use the model’s equations to calculate any ed by this model is an example as to how proposing individual’s exposure level or that of a group of indi- or using models that have not been properly vali- viduals. That is, the model lacks the requisite speci- dated can easily lead to inaccurate safety assess- ficity for application on a worker-by-worker basis. ments, improper attribution of morbidity or For the equation to accurately predict an individ- mortality in epidemiological studies, and flawed ual’s RSP/nicotine exposure level, one would have risk management decisions. to know the rate of cotinine formation for each indi- vidual. For group exposures, one would have to know how nicotine metabolism of each individual References Benowitz, N.L. (1996). Cotinine as a biomarker of environmen- group member varied before the correct individual tal tobacco smoke exposure. Epidemiologic Reviews, 18(2), 188-204. values and corresponding correct group mean val- Centers for Disease Control and Prevention (CDC). (2007, ues could be calculated. Unfortunately, the model’s May 25). Centers for Disease Control: Exposure to secondhand equations do not and cannot account for the smoke among students aged 13-15 years—worldwide, 2000-2007. Morbidity and Mortality Weekly Report, 56(20), 497-500. interindividual variations that occur in the metabo- Goodwin, R.D. (2007, May). Environmental tobacco smoke lism of nicotine to cotinine. This is a key reason as to and the epidemic of asthma in children: The role of cigarette use. why these equations lack predictive value. Annals of Allergy, Asthma & Immunology, 98(5), 447-454. Additional problems were identified for any Hodgson, M.J. (1989). Environmental tobacco smoke and the SH&E professional using urinary cotinine measure- sick building syndrome. Occupational Medicine: State of the Art Reviews, 4(4), 835-840. ments to predict exposures with these equations. For Hukkanen, J., Jacobs, P. & Benowitz, N.L. (2005). Metabolism example, the inhalation exposure estimates derived and disposition kinetics of nicotine. Pharmacological Reviews, 57, by these equations are easily skewed if the number 79-115. of individuals being sampled is not known to be rep- Lauwerys, R.R. & Hoet, P. (2001). Industrial chemical exposure: resentative of the larger group, especially if one or Guidelines for biological monitoring (3rd ed.). Boca Raton, FL: Lewis. more large urinary cotinine levels is recorded. Needham, L.L., Pirkle, J.L., Burse, V.W., et al. (1992). Case studies of relationship between external dose and internal dose. If one randomly selects two subsets of five indi- Journal of the Experimental Analysis of Behavior [Epidemiology viduals in the NIOSH casino study, the predicted Supplement(1)], 209-221. subgroup mean RSP levels will likely differ. This Repace, J.L. (2006, March 14). Report on the Empress Horsehoe occurs because a small subset of workers may not Casino (unpublished). Bowie, MD: Repace Associates Inc. capture the full extent of variation in urinary coti- Repace, J.L., Al-Delaimy, W.K. & Bernert, J.T. (2006). Correlating atmospheric and biological markers in studies of sec- nine levels occurring in the cohort (or the general ondhand tobacco smoke exposure and dose in children and adults population) from which the subset was selected. (with erratum). Journal of Occupational and Environmental Medicine, Many of the pharmacokinetic or physiologic param- 48(2), 181-194. eters used in the model’s equations will also vary Repace, J.L. & Homer, M. (2005). Laramie, Wyoming bar patron across individuals, compounding the known prob- study (WYSAC Technical Report No. CHES-517). Laramie, WY: Wyoming Survey and Analysis Center, University of Wyoming. lem with interindividual variations in the rate of Repace, J.L., Hughes, N. & Benowitz, E. (2006). Exposure to nicotine metabolism. There does not appear to be an secondhand smoke air pollution assessed from bar patrons’ uri- easy way to resolve the many identified limitations nary cotinine. Nicotine & Tobacco Research, 8(5), 701-711. inherent to this model. Repace, J.L., Jinot, J., Bayard, S., et al. (1998). Air nicotine and The present attempt to validate the model using saliva cotinine as indicators of workplace passive smoking expo- sure and risk. Risk Analysis, 18(1), 71-83. the NIOSH casino study data revealed a high error Sexton, K., Callahan, M.A. & Bryan, E.F. (1995). Estimating rate. Applying the model’s equations overstated the exposure and dose to characterize health risks: The role of human NIOSH-measured RSP levels in at least 27 of 28 indi- tissue monitoring in exposure assessment. Environmental Health viduals (only 1 of 28 individuals yielded a urinary Perspectives, 103(Suppl 3), 13–29. cotinine level that resulted in a calculated RSP level Sweda, E.L. (2001). Litigation on behalf of victims of exposure that arguably fell within the range measured by to environmental tobacco smoke: The experience from the USA. The European Journal of Public Health, 11(2), 201-205. NIOSH investigators). Trout, D. & Decker, J. (1996). Bally’s Park Place Casino Hotel, Thus, for this study, the proposed calculations Atlantic City, NJ (HETA 95-0375-2590). Cincinnati, OH: NIOSH. yield a 96% (or greater) error rate when estimating Trout, D., Decker, J., Mueller, C., et al. (1998). Exposure of the RSP levels from the collected urinary cotinine casino employees to environmental tobacco smoke. Journal of samples. For workplace safety and risk management Occupational and Environmental Medicine, 40(3), 270-276. U.S. Department of Health and Human Services (DHHS). decisions, such a high error rate in an exposure (2006). The health consequences of involuntary exposure to tobacco assessment tool is unacceptable. This high error rate smoke: A report of the Surgeon General. Washington, DC: Author, demonstrates, as much as any line of evidence, that Centers for Disease Control and Prevention, National Center for the use of this model would tend to grossly overes- Chronic Disease Prevention and Health Promotion, Office on timate nicotine/RSP levels when calculated from Smoking and Health. World Health Organization (WHO). (2007). Only 100% measured urinary cotinine levels. smoke-free environments adequately protect from dangers of sec- This analysis stresses the need for SH&E profes- ondhand smoke [Press release]. Geneva, Switzerland: Author. sionals to carefully consider the validity of any Retrieved July 25, 2008, from model that proposes to substitute exposure/dose news/releases/2007/pr26/en/index.html. 44 PROFESSIONAL SAFETY SEPTEMBER 2008