Nicholas J. Heyer

Behavioral Effects of Low-Level Exposure to Hg" Among Dentists

Abstract Exposure thresholds for health effects associated with elemental mercury (Hg∘) exposure were examined by comparing behavioral test scores of 19 exposed (mean urinary Hg = 36 μg/l) with those of 20 unexposed dentists. Thirty-six μg Hg/l is 7 times greater than the 5 μg Hg/l mean level measured in a national sample of dentists. To improve the distinction between recent and cumulative effects, the study also evaluated porphyrin concentrations in urine, which are correlated with renal Hg content (a measure of cumulative body burden). Subjects provided an on-site spot urine sample, were administered a 1-h assessment consisting of a consent form, the Profile of Mood Scales, a symptom and medical questionnaire, and 6 behavioral tests: digit-span, symbol-digit substitution, simple reaction time, the ability to switch between tasks, vocabulary, and the One Hole Test. Multivariate regression techniques were used to evaluate dose-effects controlling for the effects of age, race, gender and alcohol consumption. A dose-effect was considered statistically significant below a p value of 0.05. Significant urinary Hg dose-effects were found for poor mental concentration, emotional lability, somatosensory irritation, and mood scores. Individual tests evaluating cognitive and motor function changed in the expected directions but were not significantly associated with urinary Hg. However, the pooled sum of rank scores for combinations of tests within domains were significantly associated with urinary Hg, providing evidence of subtle preclinical changes in behavior associated with Hg exposure. Coproporphyrin, one of three urinary porphyrins altered by mercury exposure, was significantly associated with deficits in digit span and simple reaction time. The prophyrin pooled sums of rank scores were as sensitive as the urinary Hg analyses within the cognitive and motor domains but were less sensitive for the overall battery of tests. The reported effects were detected among dentists with a mean urinary Hg level of 36 μg/l, which lies between the proposed biologic thresholds of 25 and 50 μg Hg/creatinine, suggesting the need for a more comprehensive study to determine the threshold of adverse biologic effects.

Neurobehavioral effects from exposure to dental amalgam Hgo: new distinctions between recent exposure and Hg body burden

Potential toxicity from exposure to mercury vapor (Hgo) from dental amalgam fillings is the subject of current public health debate in many countries. We evaluated potential central nervous system (CNS) toxicity associated with handling Hg‐con‐ taining amalgam materials among dental personnel with very low levels of Hgo exposure (i.e., urinary Hg <4 μg/l), applying a neurobehavioral test battery to evaluate CNS functions in relation to both recent exposure and Hg body burden. New distinctions between subtle preclinical effects on symptoms, mood, motor function, and cognition were found associated with Hg body burden as compared with those associated with recent exposure. The pattern of results, comparable to findings previously reported among subjects with urinary Hg >50 μg/l, presents convincing new evidence of adverse behavioral effects associated with low Hgo exposures within the range of that received by the general population.—Echeverria, D., Aposhian, H. V., Woods, J. S., Heyer, N. J., Aposhian, M. M., Bittner, A. C., Jr. Mahurin, R. K. Neurobehavioral effects from exposure to dental amalgam Hgo: new distinctions between recent exposure and Hg body burden. FASEB J. 12, 971–980 (1998)

Mortality among firefighters from three northwestern United States cities

To explore whether exposure among firefighters to fire smoke could lead to an increased risk of cancer, lung disease, and heart disease, the mortality of 4546 firefighters who were employed by the cities of Seattle and Tacoma, WA and Portland, OR for at least one year between 1944 and 1979 were compared with United States national mortalities and with mortality of police officers from the same cities. Between 1945 and 1989, 1169 deaths occurred in the study population and 1162 death certificates (99%) were collected. Mortality due to all causes, ischaemic heart disease, and most other non-malignant diseases was less than expected based upon United States rates for white men. There was no excess risk of overall mortality from cancer but excesses of brain tumours (standardised mortality ratio (SMR) = 2.09, 95% confidence interval (95% CI) 1.3-3.2) and lymphatic and haematopoietic cancers (SMR = 1.31, 95% CI = 0.9-1.8) were found. Younger firefighters (< 40 years of age) appeared to have an excess risk of cancer (SMR = 1.45, 95% CI 0.8-2.39), primarily due to brain cancer (SMR = 3.75, 95% CI 1.2-8.7). The risk of lymphatic and haematopoietic cancers was greatest for men with at least 30 years of exposed employment (SMR = 2.05, 95% CI 1.1-3.6), especially for leukaemia (SMR = 2.60, 95% CI 1.0-5.4).

Mortality among workers in the diatomaceous earth industry.

A cohort mortality study was conducted among workers from two plants in the diatomaceous earth mining and processing industry in California. Diatomaceous earth consists of the skeletal remains of diatoms. Exposure to amorphous (non-crystalline) and crystalline silica in the form of quartz results from open pit mining and exposure to crystalline silica (principally cristobalite) occurs in the processing of the material. Lung cancer and non-malignant respiratory diseases have been the health outcomes of greatest concern. The main study cohort included 2570 white men (533 Hispanic and 2017 non-Hispanic workers) who were employed for at least 12 months cumulative service in the industry and who had worked for at least one day during the follow up period, 1942-87. Vital status was ascertained for 91% of the cohort and death certificate information was retrieved for 591 of 628 (94%) identified deaths. The all causes combined standardised mortality ratio (SMR) was slightly increased (SMR = 1.12; 628 observed) compared with rates among US white males. The principal contributors to this excess were increased risks from lung cancer (SMR = 1.43; 59 observed) and non-malignant respiratory disease (NMRD) excluding infectious diseases and pneumonia (SMR = 2.59; 56 observed). The excess of lung cancer persisted when local county rates were used for comparison (SMR = 1.59). Internal rate comparisons by Poisson regression analysis were conducted to assess potential dose-response relations for lung cancer and NMRDs. Mortality trends were examined in relation to duration of employment in dust exposed jobs and with respect to an index of cumulative exposure to crystalline silica. The crystalline silica index was a semiquantitative measure that combined information on duration of exposure, differences in exposure intensity between jobs and calendar periods, the crystalline content of the various product mixes, and the use of respiratory protection devices. Increasing gradients of risk were detected for lung cancer and NMRD with both exposure indices. The relative risk trends for lung cancer and NMRD with crystalline silica exposure lagged 15 years were respectively: 1.00, 1.19, 1.37, and 2.74, and 1.00, 1.13, 1.58, and 2.71. Based on a review of available but limited data on cigarette smoking in the cohort and from application of indirect methods for assessing confounding variables, it seems unlikely that smoking habits could account for all of the association between exposure to dust and lung cancer. The intense and poorly controlled dust exposures encountered before the 1950s were probably the most aetiologically significant contributors to risks from lung cancer and NMRDs. The absence of an excess of lung cancer among workers hired since 1960, and the finding of no deaths attributed to pneumoconiosis as an underlying cause of death among workers hired since 1950 indicate that exposure reductions in the industry during the past 40 years have been successful in reducing excess risks to workers. Further mortality follow up of the cohort and the analysis of radiographic data will be needed to determine conclusively the long term patterns of disease risks in this industry.

Behavioral Effects of Low-Level Exposure to Hg0 Among Dental Professionals: A Cross-Study Evaluation of Psychomotor Effects

A Across-study design was used to evaluate the sensitivities of five psychomotor tasks previously used to assess preclinical effects of low-level Hg0 (urinary < or =55 microg/l). Pooling dental professional subject populations from six studies conducted over the last 6 years, a larger study population was obtained with a high degree of uniformity (N = 230). The five psychomotor tests were: Intentional Hand Steadiness Test (IHST); Finger Tapping: The One-Hole Test: NES Simple Reaction Time (SRT); and Hand Tremor. Multivariate analyses were conducted following the hierarchical analysis of multiple responses (HAMR) approach. First, multiple scores of each test were combined into a single-factor (or related summary) variable and its reliability was estimated. Second. multiple regression analyses were conducted including log-transformed [Hg0]U levels, age, gender, and alcohol consumption in each model. Computed were both B and bu, the magnitudes of the log-Hg0 standardized coefficient. respectively uncorrected and corrected for dependent variable attenuation due to unreliability. Results indicated remarkable differences in the effects of relative level of Hg0 on psychomotor performance. Significant associations were found for the IHST factor (B = 0.415, p < 10(-6)), followed by finger tapping, which was relatively meager and insignificant (B 0.141, p = 0.17). The IHST results hold the greatest occupational relevance for dental professionals who rely on manual dexterity in restorative dentistry. Further, this statistical approach is recommended in future studies for condensation of multiple scores into summary scores with enhanced reliabilities useful in correcting for attenuation relationships (B(u)s) with exposure levels.

Cancer incidence among firefighters in Seattle and Tacoma, Washington (United States)

In order to determine if exposure to carcinogens in fire smoke increases the risk of cancer, we examined the incidence of cancer in a cohort of 2,447 male firefighters in Seattle and Tacoma, (Washington, USA). The study population was followed for 16 years (1974–89) and the incidence of cancer, ascertained using a population-based tumor registry, was compared with local rates and with the incidence among 1,878 policemen from the same cities. The risk of cancer among firefighters was found to be similar to both the police and the general male population for most common sites. An elevated risk of prostate cancer was observed relative to the general population (standardized incidence ratio [SIR]=1.4, 95 percent confidence interval [CI]=1.1–1.7) but was less elevated compared with rates in policement (incidence density ratio [IDR]=1.1, CI=0.7–1.8) and was not related to duration of exposure. The risk of colon cancer, although only slightly elevated relative to the general population (SIR=1.1, CI=0.7–1.6) and the police (IDR=1.3, CI=0.6–3.0), appeared to increase with duration of employment. Although the relationship between firefighting and colon cancer is consistent with some previous studies, it is based on small numbers and may be due to chance. While this study did not find strong evidence for an excess risk of cancer, the presence of carcinogens in the firefighting environment warrants periodic re-evaluation of cancer incidence in this population and the continued use of protective equipment.

QUANTIFICATION OF HISTORICAL DUST EXPOSURES IN THE DIATOMACEOUS EARTH INDUSTRY

Quantitative estimates of dust exposure in a diatomaceous earth (DE) mining and milling operation have been derived based on air sampling records for the period 1948-1988. A total of 6395 records was included in the analysis. Conversion of results obtained by particle counting, expressed as millions of particles per cubic feet (mppcf) of gravimetrically from a filter cassette and expressed as mg m-3 total, were converted to mg m-3 respirable dust using a conversion factor derived from data obtained during the same periods at the plant. Conversion factors were calculated as the average difference of means on the log scale in order to provide stable and consistent conversions and as a ratio of arithmetic means so that the results could be compared with similar studies. After converting the available data to mg m-3 respirable dust, geometric mean (geometric standard deviation) concentrations were 0.37 (2.43) during the 1950s and 0.17 (2.35) during later periods. Exposures were estimated using two linear models, one estimating the changes in concentration over time, and the other providing job-specific mean exposures during the more recent period. Extrapolation of the estimates to periods prior to the availability of any data was done using a subjectively-determined scaling factor. The average estimated respirable dust concentrations for 135 jobs were 3.55 (+/-1.25), 1.37 (+/-0.48), 0.47 (+/-0.16) and 0.29 (+/-0.10) mg m-3 prior to 1949, 1949-1953, 1954-1973 and 1974-1988, respectively. Despite the limitations of the available data, the estimation procedures used are expected to provide reasonable quantitative estimates of silica-containing dust exposure for subsequent exposure-response analyses.

Development and validation of a self-administered occupational health history questionnaire.

Although the diagnosis of work-related illness relies heavily on the occupational history, there is no validated or widely used questionnaire available to obtain this information. We designed an occupational health history questionnaire (OHHQ) in order to assess (1) its usefulness in obtaining exposure and work histories and (2) its ability to discriminate among workers with different degrees of hazardous exposure. A self-administered OHHQ was completed by 100 consecutive patients known to have a high probability of work-related disease (group 1) and by 55 consecutive workers at low risk for occupational toxic exposures (group 2). Group 1 was found to have a significantly higher number of self-assessed overall exposures (SAESs) than group 2 (p less than .001). Within group 1, scores of SAESs were highly correlated with an assessment by an industrial hygienist of the degree of hazardous exposure (p less than .001). The OHHQ can be feasibly self-administered; it has discriminant validity (correctly identifying groups of workers with high and low hazardous exposures) and convergent validity (correlating with an independent assessment of hazardous exposures).

MODIFICATION OF NEUROBEHAVIORAL EFFECTS OF MERCURY BY A GENETIC POLYMORPHISM OF COPROPORPHYRINOGEN OXIDASE IN CHILDREN

Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is the identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. We examined the hypothesis that CPOX4, a genetic variant of the heme pathway enzyme coproporphyrinogen oxidase (CPOX) that affects susceptibility to mercury toxicity in adults, also modifies the neurotoxic effects of Hg in children. Five hundred seven children, 8-12 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings in children. Subjects were evaluated at baseline and at 7 subsequent annual intervals for neurobehavioral performance and urinary mercury levels. Following the completion of the clinical trial, genotyping assays for CPOX4 allelic status were performed on biological samples provided by 330 of the trial participants. Regression modeling strategies were employed to evaluate associations between CPOX4 status, Hg exposure, and neurobehavioral test outcomes. Among girls, few significant CPOX4-Hg interactions or independent main effects for Hg or CPOX4 were observed. In contrast, among boys, numerous significant interaction effects between CPOX4 and Hg were observed spanning all 5 domains of neurobehavioral performance. All underlying dose-response associations between Hg exposure and test performance were restricted to boys with the CPOX4 variant, and all of these associations were in the expected direction where increased exposure to Hg decreased performance. These findings are the first to demonstrate genetic susceptibility to the adverse neurobehavioral effects of Hg exposure in children. The paucity of responses among same-age girls with comparable Hg exposure provides evidence of sexual dimorphism in genetic susceptibility to the adverse neurobehavioral effects of Hg in children and adolescents.

Urinary porphyrin excretion in neurotypical and autistic children

Background Increased urinary concentrations of pentacarboxyl-, precopro- and copro-porphyrins have been associated with prolonged mercury (Hg) exposure in adults, and comparable increases have been attributed to Hg exposure in children with autism (AU). Objectives This study was designed to measure and compare urinary porphyrin concentrations in neurotypical (NT) children and same-age children with autism, and to examine the association between porphyrin levels and past or current Hg exposure in children with autism. Methods This exploratory study enrolled 278 children 2–12 years of age. We evaluated three groups: AU, pervasive developmental disorder-not otherwise specified (PDD-NOS), and NT. Mothers/caregivers provided information at enrollment regarding medical, dental, and dietary exposures. Urine samples from all children were acquired for analyses of porphyrin, creatinine, and Hg. Differences between groups for mean porphyrin and Hg levels were evaluated. Logistic regression analysis was conducted to determine whether porphyrin levels were associated with increased risk of autism. Results Mean urinary porphyrin concentrations are naturally high in young children and decline by as much as 2.5-fold between 2 and 12 years of age. Elevated copro- (p < 0.009), hexacarboxyl- (p < 0.01) and pentacarboxyl- (p < 0.001) porphyrin concentrations were significantly associated with AU but not with PDD-NOS. No differences were found between NT and AU in urinary Hg levels or in past Hg exposure as determined by fish consumption, number of dental amalgam fillings, or vaccines received. Conclusions These findings identify disordered porphyrin metabolism as a salient characteristic of autism. Hg exposures were comparable between diagnostic groups, and a porphyrin pattern consistent with that seen in Hg-exposed adults was not apparent.