Diana Echeverria

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)

Psychophysiological Mediators of Caregiver Stress and Differential Cognitive Decline

The authors examined relationships between chronic stress and cognitive decline and whether such relationships were mediated by psychophysiological factors. Ninety-six caregivers of spouses with Alzheimers disease (AD) were compared with 95 similar noncaregiver spouses. All were free of diabetes. Although the groups started similarly, over 2 years caregivers declined by a small but significant amount (1 raw score point and 4 percentile points, each p<.05) on Shipley Vocabulary. In contrast, noncaregivers did not change. Higher hostile attribution (beta=-.09; p<.05) and metabolic risk (beta=-.10; p<.05) in caregivers mediated the cognitive decline. This is the first study of cognitive decline and mediators in caregivers. This work has implications for caregiver and care-recipient health and for research on cognition, psychophysiology, diabetes, and AD.

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.

Depressed Mood Mediates Decline in Cognitive Processing Speed in Caregivers

PURPOSE Very few studies have examined cognitive decline in caregivers versus noncaregivers, and only 1 study has examined mediators of such decline. We evaluated the relationship between caregiver status and decline on the digit symbol test (DST; a measure of processing speed, attention, cognitive-motor translation, and visual scanning) and whether this relationship was mediated by depressed mood. DESIGN AND METHODS Caregivers for spouses with Alzheimers disease (n = 122) were compared with demographically similar noncaregiver spouses (n = 117) at study entry (Time 1 = T1), T2 (1 year later), and T3 (2 years after T1). RESULTS Caregivers had lower DST scores and higher Hamilton depression scores at T1, T2, and T3 than noncaregivers (all p < .05). Hierarchical linear modeling revealed that although caregivers started well below noncaregivers, they experienced a more rapid rate of decline than noncaregivers (p = .047). Caregivers declined 4.5 times faster than noncaregivers. Greater depressed mood at T1 (p < .01) and T2 (p < .01) predicted DST decline and mediated DST decline in caregivers vs. noncaregivers. IMPLICATIONS Depressed mood in caregivers relative to noncaregivers may influence their greater risk for DST decline. This is important because the DST predicts problem solving and everyday functions necessary for independent living and the potential well-being of their care recipients.

Occupational exposures to solvents and aluminium and estimated risk of Alzheimer's disease.

OBJECTIVES: To study the role of occupational exposures to solvents and aluminium in the aetiology of Alzheimers disease (AD). An industrial hygienist rated exposure. METHODS: 89 subjects diagnosed with probable AD were matched by age, sex, and type of informant to 89 controls. Subjects were identified from a large health maintenance organisation in Seattle, WA. A complete occupational history was obtained from spouses of cases and controls as well as from controls themselves. After the interview an industrial hygienist, blinded to case-control status, rated exposures. RESULTS: Non-significant associations were found between AD and ever having been occupationally exposed to solvents (odds ratio (OR) 1.77, 95% confidence interval (95% CI) 0.81 to 3.90) and aluminium (OR 1.46, 95% CI 0.62 to 3.42). Although an increasing risk was found with increasing number of years of exposure to solvents, there was an inverse association between exposure intensity and AD, and measures of cumulative exposure taking into account both intensity and duration of exposure were not significant. Analysis of the age at which half the cumulative exposure to solvents was achieved showed that an older age incurred a greater risk of AD than a younger age. However, the total amount of exposure carried no risk. CONCLUSIONS: The results suggest that lifetime occupational exposure to solvents and aluminium are not likely to be important risk factors for Alzheimers disease.

A behavioral evaluation of PCE exposure in patients and dry cleaners : a possible relationship between clinical and preclinical effects

Long-term deficits in visuospatial function and memory and disturbances in mood have been clinically identified and followed in four patients occupationally exposed to perchloroethylene (PCE). A frontal/ limbic hypothesis is offered as the site of pathology. A separate study among 65 dry cleaners was conducted to provide similar evidence of impairment, suggesting a continuum between clinical and preclinical effects. Three exposure zones were identified for the counter clerks, pressers, and operators corresponding to air levels of 11.2, 23.2, and 40.8 ppm. Decrements were found for visual reproductions (14.4%), the number correct (6.7%) and the latency (10%) for pattern memory, and the number correct (3.9%) for pattern recognition. Chronic, life-long deficits appear below 50 ppm and require at least 3 years of exposure. A reexamination of the OSHA standard is recommended and shows that behavioral testing can be used as an early indicator of more serious clinical effects.

Hepatic ultrasonic changes in workers exposed to perchloroethylene.

OBJECTIVE--To determine if subclinical hepatotoxicity is associated with exposure to perchloroethylene at concentrations commonly experienced in the workplace, and whether surveillance with serum hepatic transaminase activity underestimates such effects. METHODS--Hepatic parenchymal echogenicity on ultrasonography and serum hepatic transaminase activity were compared in 29 community based dry cleaning operators exposed to perchloroethylene, and a control group of 29 non-exposed laundry workers. Perchloroethylene exposure was assessed by work history and air monitoring. RESULTS--Mean hepatic transaminase activities were minimally increased in dry cleaners compared with laundry workers. Increased alanine aminotransferase activities, between 1.0 and 1.5 times the normal limits, were found in five of 27 (19%) dry cleaners compared with one of 26 (4%) laundry workers. In contrast, diffuse parenchymal changes in echogenicity, as determined by hepatic ultrasonography, were increased nearly twofold in dry cleaners, occurring in 18 of 27 (67%) dry cleaners compared with 10 of 26 (39%) laundry workers (P < 0.05), and were most strongly associated with increased perchloroethylene exposure in older dry to dry or wet transfer operations (odds ratio 4.2, 95% confidence interval 1.1-15.3). Mean eight hour time weighted average perchloroethylene exposure for dry cleaners was 16 ppm, which is less than the permissible exposure limit of 100 ppm in the United States. CONCLUSIONS--It was concluded that mild to moderate hepatic parenchymal changes occur more frequently in workers exposed to perchloroethylene than in populations not exposed to chemical solvents, and that these effects are underestimated by serum hepatic transaminase activity.

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.