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Shift in neurobehavioral performance with exposure

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Performance in exposed population

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APHA - November 4-8, 2006 - Boston MAAPHA - November 4-8, 2006 - Boston MA

Neurological Risk Assessment: The Benchmark Dose Method and Deficits in Bridge WeldersNeurological Risk Assessment: The Benchmark Dose Method and Deficits in Bridge Welders Robert M. Park, NIOSH*, Cincinnati OH Rosemarie Bowler, San Francisco State University Donald E. Eggerth, NIOSH* *

Emily Diamond, The Wright Institute, Berkeley CA Katie J. Spencer, Miami University, Oxford OH Donald Smith and Robert Gwiazda UC, Santa Cruz CA

Education and Information Division, Risk Evaluation Branch*/ Training Research and Evaluation Branch** , NIOSH, Cincinnati

Occupational risk assessment typically estimates excess life-time risk for onset of a chronic disease or fatal health outcome in relation to a fixed life-time workplace exposure. Excess lifetime risks are often considered acceptable if they are < 1/1000. For sub-clinical health effects such as respiratory or neurobehavioral changes measured as continuous variables, the Benchmark Dose (BMD) method examines exposure-induced shifts in outcome distributions (Fig. 1). But this poses some issues: 1) one must define a threshold for impairment (often the 5th percentile of performance in an unexposed population) and then calculate at what exposure there is a 1, 5, or 10% excess impairment above that threshold.; and 2) one must specify what increases in impairment are acceptable. Individuals falling below the 5th percentile in a normal population may have other identifiable risk factors that themselves merit prevention; and allowing an increase of 5% impairment (above a background 5%) is equivalent to permitting a relative risk of 2.0 and 50/1000 excess risk.

Figure 1

Figure 2 Blood Mn (ug/l) and adjusted welding duration (mos)

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RESULTS

Linear regression models were used to predict managanese blood levels and test performance scores in relation to duration of Mn exposure and cumulative Mn exposure. Manganese blood levels increased with adjusted exposure duration [Mn(B)=6.9800+0.1507adjDur, Rsq=0.137, p=0.0186] (Fig.2). The association with cumMn was only very slightly stronger [Mn(B)= 7.701+ 0.7178cumMn, Rsq=0.139, p=0.0177]. Performance on test ACT3, a test of short-term auditory memory and divided attention (normal=0.0), was strongly associated with adjusted duration [ACT3=1.050-0.1319adjDur, Rsq=0.26, p=0.0002 one-tailed] (Fig. 3) and considerably less strongly with cumulative Mn [ACT3=-.04037-0.3197cumMn, Rsq=0.07, p=0.04 one-tailed ]. Similarly, performance on the REYI, a test of short-term memory and visuomotor coordination (normal=50), was also most associated with adj. exposure duration [REYI=50.77-0.730adjDur, Rsq=0.11, p=0.015 one-tailed] (Fig. 4) and less strongly with an exposure metric. In the best fitting model cum Mn was calculated with a 30 day half-life [REYI=41.35-35.42cumMn(30), Rsq=0.07, p=0.045 one-tailed] (Fig.5). In this model, the lowered estimate of baseline performance (intercept: 41.4 vs 50.8) could represent exposure misclassification or possibly residual performance deficit in workers whose only exposure was several months prior to neurobehavioral assessment. A similar pattern was observed for WMI, a test of memory, concentration and attention, with a somewhat stronger association with adj. exposure duration [WMI=102.5-0.711adjDur, Rsq=0.12, p=0.013 one-tailed] (Fig. 6) than with cumulative exposure (also with 30 day half-life) [WMI=93.79-41.422cumMn(30), Rsq=0.10, p=0.023 one-tailed].

Using the results of regression models, and deriving predicted distributions of performance as a function of exposure duration or cumulative exposure, the proportions of exposed populations falling below variously defined impairment thresholds were calculated. Benchmark doses – exposure levels sustained over a two year period – at which specified excess risk of impairment would be predicted are shown in Table 1. For a 5% excess risk of impairment above a threshold defined at the lower 5%ile in an unexposed population, the benchmark Mn concentrations ranged from 0.030 mg/m3 (REYI and cum. Mn) to 0.092 mg/m3 (WMI and Adj Duration). Defining impairment at a higher threshold of poor performance, that is including less severe deficits (e.g., at 10th %ile instead of 5th %ile), produced lower benchmark doses. The predicted WMI distributions for various exposure levels are shown in Figure 7.

Figure 3 ACT3 Performance and adjusted welding duration (normal ~ N(0,1)

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Table 1 Benchmark Dose calculations (Mn, mg/m3)

Excess Risk (%)

Impairment Threshold Assumed (%)

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ACT and adj. Exposure Duration 1 0.025 0.012 0.008

2 0.042 0.022 0.015

5 0.072 0.042 0.032

10 0.102 0.069 0.055

     

ACT and cum. Mn Exposure 1 0.010 0.007 0.006

2 0.020 0.014 0.012

5 0.048 0.033 0.030

10 0.086 0.064 0.058

REYI and adj. Exposure Duration 1 0.015 0.008 0.005

2 0.032 0.015 0.012

5 0.065 0.039 0.028

10 0.105 0.069 0.055     

REYI and cum. Mn Exposure (30 d halflife) 1 0.009 0.006 0.006

2 0.018 0.012 0.011

5 0.042 0.030 0.028

10 0.078 0.059 0.055     

WMI and adj. Exposure Duration 1 0.095 0.028 0.015

2 0.132 0.049 0.028

5 0.192 0.092 0.059

10 0.246 0.139 0.095     

WMI and cum. Mn Exposure (30 d halflife) 1 0.039 0.011 0.007

2 0.065 0.022 0.013

5 0.118 0.048 0.032

10 >0.250 0.085 0.060

Predicted Working Memory Index distributions on cumulative exposure

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Distributions for 2 yrs at air concentrations: Mn=0.0, 0.02, 0.05, 0.10, 0.15 mg/m3

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Figure 7

Figure 4 REYI Test and adjusted welding duration (normal ~ N(50,10) )

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Figure 5 REYI Test and cumulative Mn (30 day half-life)

Figure 6 WMI Test and adjusted welding duration (normal ~ N(100,15)

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Bay Bridge Project source: www.newbaybridge.org

DISCUSSION

The choice of what constitutes impairment requires clinical judgement for which there is ample precedent from inverstigations involving lead and other neurotoxicants. The issue of reversibility could not be addressed in the current study although follow-up of this population may provide some insights. The observation that duration of exposure was as good or better than cumualtive exposure as a predictor of neurobehavioral effects implies that considerable exposure misclassification may be present or that the exposure metrics, such as cumulative exposure, are not optimum.

CONCLUSION

Neurobehavioral effects are being observed at far below the current OSHA standard for Mn (5.0 mg/m3) and probably below the Cal OSHA standard (0.2 mg/m3). Studies are needed to better characterize Mn exposure history and better decribe both the short- and long-term consequences of exposure to Mn fume.

1 Park, R.M., Bowler, R.M , Eggerth, D.E., Diamond, E, Spence,r K.J., Smith, D., Gwiazda, R. “Issues in Neurological Risk Assessment for Occupational Exposures: The Bay Bridge Welders.” NeuroToxicology 2006; 27:373-384.

2. Bowler RM, Roels HA, Nakagawa S, Drezgic M, Diamond E, Park R, Koller W, Russell P Bowler RP, Mergler D, Bouchard M, Smith D, Gwiazda R, Doty RL. Dose-Effect Relations Between Manganese Exposure And Neurological, Neuropsychological And Pulmonary Function In Confined Space Bridge Welders. Occup Environ Med, accepted for publication Oct. 3, 2006.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health

High manganese exposures in populations such as ferroalloy production have been associated with symptoms of parkinsonism and manganism, and signs and symptoms consistent with parkinsonism have been reported in some welder populations. Neurobehavioral assessments using a battery of tests were conducted for 48 California bridge welders exposed to manganese in confined spaces for up to two years. Exposures ranged 0.1-0.4 mg/m3. Results for four tests (Rey-Osterrieth Complex Figure Test, Working Memory Index, Stroop Color Word Test and Auditory Consonant Trigrams Test) were used in the benchmark dose procedure and reported previously (1,2). That analysis, which used minimal work history, and environmental data covering only 17 months of the 2 yr period, observed excess impairment defined as performance below the 5th percentile of normal, at the current Cal OSHA standard (0.2 mg/m3, 8 hr TWA), ranging 15 - 32%. These results suggested unacceptable risks of a possible parkinsonian syndrome at the current OSHA PEL for manganese (5.0 mg/m3, 15 min) and likely at the Cal OSHA PEL as well.

METHODS

For this analysis, a more detailed history of each worker’s activities over time was available (automatic vs. manual welding; location: in bridge piling or in associated chambers) as was environmental sampling data from the entire 2 yr period. The BMD procedure is reported for three outcomes: Auditory Consonant Trigrams Test (3 seconds), ACT3, Rey-Osterrieth Complex Figure Test (immediate copy), REYI, and Working Memory Index, WMI. In every case, a lower test score represented poorer performance. Test performance was analyzed in relation to duration of employment on this bridge project, and in relation to duration actually exposed to welding with adjustment for average length of working day and days worked per week. The exposure metric used was cumulative exposure to total airborne manganese (Mn mg/m3) as well as an alternate metric that was calculated assuming depletion of the manganese effect with various half-lives following exposure. For models based on durations, a global air concentration of 0.20 mg/m3 was assumed (the current Cal OSHA standard and a rough estimate of average exposures in this population).