Robert M. Park

Dose-effect relationships between manganese exposure and neurological, neuropsychological and pulmonary function in confined space bridge welders

Background: Although adverse neuropsychological and neurological health effects are well known among workers with high manganese (Mn) exposures in mining, ore-processing and ferroalloy production, the risks among welders with lower exposures are less well understood. Methods: Confined space welding in construction of a new span of the San Francisco–Oakland Bay Bridge without adequate protection was studied using a multidisciplinary method to identify the dose–effect relationship between adverse health effects and Mn in air or whole blood. Bridge welders (n = 43) with little or no personal protection equipment and exposed to a welding fume containing Mn, were administered neurological, neuropsychological, neurophysiological and pulmonary tests. Outcome variables were analysed in relation to whole blood Mn (MnB) and a Cumulative Exposure Index (CEI) based on Mn-air, duration and type of welding. Welders performed a mean of 16.5 months of welding on the bridge, were on average 43.8 years of age and had on average 12.6 years of education. Results: The mean time weighted average of Mn-air ranged from 0.11–0.46 mg/m3 (55% >0.20 mg/m3). MnB >10 µg/l was found in 43% of the workers, but the concentrations of Mn in urine, lead in blood and copper and iron in plasma were normal. Forced expiratory volume at 1s: forced vital capacity ratios (FEV1/FVC) were found to be abnormal in 33.3% of the welders after about 1.5 years of welding at the bridge. Mean scores of bradykinesia and Unified Parkinson Disease Rating Scale exceeded 4 and 6, respectively. Computer assisted tremor analysis system hand tremor and body sway tests, and University of Pennsylvania Smell Identification Test showed impairment in 38.5/61.5, 51.4 and 88% of the welders, respectively. Significant inverse dose–effect relationships with CEI and/or MnB were found for IQ (p⩽0.05), executive function (p⩽0.03), sustaining concentration and sequencing (p⩽0.04), verbal learning (p⩽0.01), working (p⩽0.04) and immediate memory (p⩽0.02), even when adjusted for demographics and years of welding before Bay Bridge. Symptoms reported by the welders while working were: tremors (41.9%); numbness (60.5%); excessive fatigue (65.1%); sleep disturbance (79.1%); sexual dysfunction (58.1%); toxic hallucinations (18.6%); depression (53.5%); and anxiety (39.5%). Dose–effect associations between CEI and sexual function (p<0.05), fatigue (p<0.05), depression (p<0.01) and headache (p<0.05) were statistically significant. Conclusions: Confined space welding was shown to be associated with neurological, neuropsychological and pulmonary adverse health effects. A careful enquiry of occupational histories is recommended for all welders presenting with neurological or pulmonary complaints, and a more stringent prevention strategy should be considered for Mn exposure due to inhalation of welding fume.

Comparing median lethal concentration values using confidence interval overlap or ratio tests

Experimenters in toxicology often compare the concentration-response relationship between two distinct populations using the median lethal concentration (LC50). This comparison is sometimes done by calculating the 95% confidence interval for the LC50 for each population, concluding that no significant difference exists if the two confidence intervals overlap. A more appropriate test compares the ratio of the LC50s to 1 or the log(LC50 ratio) to 0. In this ratio test, we conclude that no difference exists in LC50s if the confidence interval for the ratio of the LC50s contains 1 or the confidence interval for the log(LC50 ratio) contains 0. A Monte Carlo simulation study was conducted to compare the confidence interval overlap test to the ratio test. The confidence interval overlap test performs substantially below the nominal alpha = 0.05 level, closer to p = 0.005; therefore, it has considerably less power for detecting true differences compared to the ratio test. The ratio-based method exhibited better type I error rates and superior power properties in comparison to the confidence interval overlap test. Thus, a ratio-based statistical procedure is preferred to using simple overlap of two independently derived confidence intervals.

Breast cancer risk in relation to occupations with exposure to carcinogens and endocrine disruptors: a Canadian case–control study

BackgroundEndocrine disrupting chemicals and carcinogens, some of which may not yet have been classified as such, are present in many occupational environments and could increase breast cancer risk. Prior research has identified associations with breast cancer and work in agricultural and industrial settings. The purpose of this study was to further characterize possible links between breast cancer risk and occupation, particularly in farming and manufacturing, as well as to examine the impacts of early agricultural exposures, and exposure effects that are specific to the endocrine receptor status of tumours.Methods1005 breast cancer cases referred by a regional cancer center and 1146 randomly-selected community controls provided detailed data including occupational and reproductive histories. All reported jobs wereindustry- and occupation-coded for the construction of cumulative exposure metrics representing likely exposure to carcinogens and endocrine disruptors. In a frequency-matched case–control design, exposure effects were estimated using conditional logistic regression.ResultsAcross all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk (OR = 1.42; 95% CI, 1.18-1.73, for 10 years exposure duration). Specific sectors with elevated risk included: agriculture (OR = 1.36; 95% CI, 1.01-1.82); bars-gambling (OR = 2.28; 95% CI, 0.94-5.53); automotive plastics manufacturing (OR = 2.68; 95% CI, 1.47-4.88), food canning (OR = 2.35; 95% CI, 1.00-5.53), and metalworking (OR = 1.73; 95% CI, 1.02-2.92). Estrogen receptor status of tumors with elevated risk differed by occupational grouping. Premenopausal breast cancer risk was highest for automotive plastics (OR = 4.76; 95% CI, 1.58-14.4) and food canning (OR = 5.70; 95% CI, 1.03-31.5).ConclusionsThese observations support hypotheses linking breast cancer risk and exposures likely to include carcinogens and endocrine disruptors, and demonstrate the value of detailed work histories in environmental and occupational epidemiology.

Exposure to crystalline silica, silicosis, and lung disease other than cancer in diatomaceous earth industry workers: a quantitative risk assessment.

Objectives: To estimate excess lifetime risk of (a) mortality from lung disease other than cancer (LDOC), and, (b) onset of radiographic silicosis, arising from occupational exposure to respirable crystalline silica dust. Methods: Data from a cohort of California diatomaceous earth mining and processing workers exposed to crystalline silica dust (mainly as cristobalite) were reanalyzed with Poisson regression methods with internal and external adjustments for potential confounding by calendar time, age, smoking, Hispanic ethnicity, and time since first observation. Model fit was evaluated by comparing deviances and fitting cubic spline models. Lifetime risks of death from LDOC and radiographic silicosis were estimated up to age 85 with an actuarial approach accounting for competing causes of death. Results: For deaths due to LDOC, a linear relative rate model gave the best fit in Poisson regression analyses. At the mean cumulative exposure of LDOC cases to silica, after adjustment for smoking, the estimated rate ratio was 4.2 (p<0.0001); at the maximum cumulative exposure of cases, the rate ratio was 18.4. The excess lifetime risk for white men exposed to respirable cristobalite dust for 45 years at the current permissible exposure limit (PEL; about 0.05 mg/m3) of the Occupational Safety and Health Administration was 54/1000 (95% confidence interval (95% CI) 17 to 150). For 70 incident cases of radiographic silicosis largely manifest before the end of employment, the best fit was also the linear relative rate model, predicting a rate ratio of 25.6 for silicosis at the mean cumulative exposure of the cases (p<0.0001). The excess lifetime risk for silicosis at the current PEL was 75/1000. Conclusion: Current occupational health standards for crystalline silica permit risks of lung disease other than cancer far in excess of what is usually considered acceptable by the Occupational Safety and Health Administration (a lifetime risk of less than one in a thousand deaths).

A comparison of PMRs and SMRs as estimators of occupational mortality.

Standardized mortality ratios (SMRs) for occupational diseases are confounded by health differences between industrial and general populations. In 109 industrial cohorts largely free of work-related mortality, these selection effects were sizable for both malignant and nonmalignant outcomes. All-cancer SMRs were considerably less than 1.0 for many cohorts, and lung cancer was subject to almost as much selection-derived confounding as nonmalignant disease. Standardized proportional mortality ratios (PMRs) (approximated by relative SMRs (RSMRs)) were less confounded than SMRs in estimating occupational risk. PMRs appeared to overestimate cancer mortality on average by 6%, while SMRs underestimated by 13%. PMRs underestimated nonmalignant respiratory disease by 16 percent but SMRs underestimated by 39 percent. The sources of confounding, in addition to selection on health status at hire, most likely include social class. SMRs, in the absence of internal population comparisons, would fail to detect both malignant and nonmalignant work-related mortality in many industrial cohorts

A survey of mortality at two automotive engine manufacturing plants

Mortality at two engine plants was analyzed using proportional mortality and logistic regression models of mortality odds ratios to expand previous observations of increased cancers of the stomach, pancreas, and bladder, and cirrhosis of the liver among workers exposed to machining fluids. Causes of death and work histories were available for 1,870 decendents. There was a significant excess of deaths coded as diabetes for white men in both plants (PMR = 25/16.7 = 1.5, 95% CI = 1.02, 2.20), and a deficit of respiratory diseases. Black men had fewer than expected diabetes deaths and more emphysema deaths. Elevated PMRs for cancers of the stomach, pancreas, prostate, bladder, and kidney were not statistically significant in plantwide populations. However, stomach cancer mortality increased with duration in camshaft and crankshaft production at Plant 1 (OR = 5.1, 95% CI = 1.6, 17; at mean duration of exposed cases), and among tool room workers (OR = 6.3, 95% CI = 1.3, 31), but these results were based on five cases. Nitrosamines were probably present in camshaft and crankshaft grinding at Plant 1. Pancreas cancer risk increased among workers at both plants ever employed in inspection (OR = 2.5, 16), in machining with straight oil (OR = 3.6, 95% CI = 1.04, 12), or in skilled trades (OR = 2.9, 95% CI = 1.1, 7.5). Lung cancer increased in cylinder head machining (OR = 3.9, 95% CI = 1.4, 11), millwright work (OR = 3.8, 95% CI = 1.6, 9.0), and in Plant 2 generally (OR = 1.45, 95% CI = 0.97, 2.2). Potential lung carcinogens included heat treatment emissions, chlorinated oils, and coal tar fumes (millwrights). Bladder cancer increased with duration among workers grinding in straight oil MF (OR = 3.0, 95% CI = 1.15, 7.8) and in machining/heat-treat operations (OR = 2.9, 95% CI = 1.14, 7.2).

Cumulative trauma disorders of the hand and wrist in the auto industry.

Surveillance for cumulative trauma disorders (CTDs) of the hand and wrist was carried out in five US automotive plants from 1985 to 1986, using Occupational Safety and Health Administration (OSHA) Form 200 injury and illness logs and medical insurance claims. Results using both record sources indicated that hand and wrist disorders may be more common in foundries than in other types of automotive plants. Similarly, in assembly plants, employees in certain departments appeared to be at higher risk for CTDs. Although our results are based on small numbers of cases, they suggest plants and departments that might be targeted for more detailed investigation.

Cadmium and lung cancer mortality accounting for simultaneous arsenic exposure

Objectives Prior investigations identified an association between airborne cadmium and lung cancer but questions remain regarding confounding by arsenic, a well-established lung carcinogen. Methods A cadmium smelter population exhibiting excess lung cancer was re-analysed using a retrospective exposure assessment for arsenic (As), updated mortality (1940–2002), a revised cadmium (Cd) exposure matrix and improved work history information. Results Cumulative exposure metrics for both cadmium and arsenic were strongly associated making estimation of their independent effects difficult. Standardised mortality ratios (SMRs) were modelled with Poisson regression with the contribution of arsenic to lung cancer risk constrained by exposure–response estimates previously reported. The results demonstrate (1) a statistically significant effect of Cd independent of As (SMR=3.2 for 10 mg-year/m3 Cd, p=0.012), (2) a substantial healthy worker effect for lung cancer (for unexposed workers, SMR=0.69) and (3) a large deficit in lung cancer mortality among Hispanic workers (SMR=0.27, p=0.009), known to have low lung cancer rates. A supralinear dose-rate effect was observed (contribution to risk with increasing exposure intensity has declining positive slope). Lung cancer mortality was somewhat better predicted using a cadmium burden metric with a half-life of about 20–25 years. Conclusions These findings support an independent effect for cadmium in risk of lung cancer mortality. 1/1000 excess lifetime risk of lung cancer death is predicted from an airborne exposure of about 2.4 μg/m3 Cd.

Exposure-response relationship and risk assessment for cognitive deficits in early welding-induced manganism.

Objective: The exposure-response relationship for manganese (Mn)-induced adverse nervous system effects is not well described. Symptoms and neuropsychological deficits associated with early manganism were previously reported for welders constructing bridge piers during 2003 to 2004. A reanalysis using improved exposure, work history information, and diverse exposure metrics is presented here. Methods: Ten neuropsychological performance measures were examined, including working memory index (WMI), verbal intelligence quotient, design fluency, Stroop color word test, Rey-Osterrieth Complex Figure, and Auditory Consonant Trigram tests. Mn blood levels and air sampling data in the form of both personal and area samples were available. The exposure metrics used were cumulative exposure to Mn, body burden assuming simple first-order kinetics for Mn elimination, and cumulative burden (effective dose). Benchmark doses were calculated. Results: Burden with a half-life of about 150 days was the best predictor of blood Mn. WMI performance declined by 3.6 (normal = 100, SD = 15) for each 1.0 mg/m3 × mo exposure (P = 0.02, one tailed). At the group mean exposure metric (burden; half-life = 275 days), WMI performance was at the lowest 17th percentile of normal, and at the maximum observed metric, performance was at the lowest 2.5 percentiles. Four other outcomes also exhibited statistically significant associations (verbal intelligence quotient, verbal comprehension index, design fluency, Stroop color word test); no dose-rate effect was observed for three of the five outcomes. Conclusions: A risk assessment performed for the five stronger effects, choosing various percentiles of normal performance to represent impairment, identified benchmark doses for a 2-year exposure leading to 5% excess impairment prevalence in the range of 0.03 to 0.15 mg/m3, or 30 to 150 &mgr;g/m3, total Mn in air, levels that are far below those permitted by current occupational standards. More than one-third of workers would be impaired after working 2 years at 0.2 mg/m3 Mn (the current threshold limit value).

Neurobehavioral Deficits and Parkinsonism in Occupations with Manganese Exposure: A Review of Methodological Issues in the Epidemiological Literature

Exposure to manganese (Mn) is associated with neurobehavioral effects. There is disagreement on whether commonly occurring exposures in welding, ferroalloy, and other industrial processes produce neurologically significant neurobehavioral changes representing parkinsonism. A review of methodological issues in the human epidemiological literature on Mn identified: (1) studies focused on idiopathic Parkinson disease without considering manganism, a parkinsonian syndrome; (2) studies with healthy worker effect bias; (3) studies with problematic statistical modeling; and (4) studies arising from case series derived from litigation. Investigations with adequate study design and exposure assessment revealed consistent neurobehavioral effects and attributable subclinical and clinical signs and symptoms of impairment. Twenty-eight studies show an exposure-response relationship between Mn and neurobehavioral effects, including 11 with continuous exposure metrics and six with three or four levels of contrasted exposure. The effects of sustained low-concentration exposures to Mn are consistent with the manifestations of early manganism, i.e., consistent with parkinsonism. This is compelling evidence that Mn is a neurotoxic chemical and there is good evidence that Mn exposures far below the current US standard of 5.0 mg/m3 are causing impairment.