Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on tissue and urine mercury levels following prolonged methylmercury exposure in rats.

Methylmercury, a potent neurotoxicant, accumulates in the brain as well as the kidney during chronic exposure. We evaluated the capacity of 2,3-dimercapto-1-propanesulfonic acid (DMPS), a tissue-permeable metal chelator, to reduce brain, kidney, and blood Hg levels and to promote Hg elimination in urine following exposure of F-344 rats to methylmercury hydroxide (MMH) (10 ppm) in drinking water for up to 9 weeks. Inorganic (Hg2+) and organic (CH3Hg+) mercury species in urine and tissues were assayed by cold vapor atomic fluorescence spectroscopy (CVAFS). Following MMH treatment for 9 weeks, Hg2+ and CH3Hg+ concentrations were 0.28 and 4.80 microg/g in the brain and 51.5 and 42.2 microg/g in the kidney, respectively. Twenty-four hours after ip administration of a single DMPS injection (100 mg/kg), kidney Hg2+ and CH3Hg+ declined 38% and 59%, whereas brain mercury levels were slightly increased, attributable entirely to the CH3Hg+ fraction. Concomitantly, Hg2+ and CH3Hg+ in urine increased by 7.2- and 28.3-fold, respectively, compared with prechelation values. A higher dose of DMPS (200 mg/kg) was no more effective than 100 mg/kg in promoting mercury excretion. In contrast, consecutive DMPS injections (100 mg/kg) given at 72-h intervals significantly decreased total mercury concentrations in kidney, brain, and blood. However, the decrease in brain and blood mercury content was restricted entirely to the CH3Hg+ fraction, consistent with the slow dealkylation rate of MMH in these tissues. Mass balance calculations showed that the total amount of mercury excreted in the urine following successive DMPS injections corresponds quantitatively to the total amount of mercury removed from the kidney, brain, and blood of MMH-exposed rats. These findings confirm the efficacy of consecutive DMPS treatments in decreasing mercury concentrations in target tissue and in reducing overall mercury body burden. They demonstrate further that the capacity of DMPS to deplete tissue Hg2+ is highly tissue-specific and reflects the relative capacity of the tissue for methylmercury dealkylation. In light of this observation, the inability of DMPS to reduce Hg2+ levels in brain or blood may explain the inefficacy of DMPS and similar chelating agents in the remediation of neurotoxicity associated with prolonged MMH exposure.

Quantitative evaluation of urinary porphyrins as a measure of kidney mercury content and mercury body burden during prolonged methylmercury exposure in rats.

Changes in urinary porphyrin excretion patterns (porphyrin profiles) during prolonged mercury exposure are attributable to mercury accumulation in the kidney and to consequent effects of Hg2+ on renal porphyrin metabolism. In the present study, we evaluated the quantitative relationship of urinary porphyrin concentrations to mobilizable renal mercury content, using the metal chelator 2,3-dimercapto-1-propanesulfonic acid (DMPS) to modulate kidney mercury levels. Rats exposed to methylmercury hydroxide (MMH) at 10 ppm in drinking water for 6 weeks were treated with up to 3 consecutive doses of DMPS (100mg/kg, ip) at 72-h intervals. Consistent with previous findings, the concentrations of pentacarboxyl- (5-) and copro- (4-) porphyrins and of an atypical porphyrin specific to mercury exposure, precoproporphyrin, were significantly elevated in urine of MMH-exposed rats, compared with that of rats exposed to distilled water (dH2O) for the same period. Consecutive DMPS treatments of MMH-exposed rats significantly decreased kidney concentrations of total, as well as Hg2+ and CH3Hg+ species, and promoted increased urinary mercury excretion. Concomitantly, DMPS treatment decreased both kidney and urinary porphyrin concentrations, consistent with depletion of renal mercury levels. Regression analyses demonstrated a high correlation (r approximately 0.9) between prechelation urinary porphyrins and postchelation urinary mercury levels and also between prechelation urinary porphyrins and prechelation kidney mercury concentrations. These findings demonstrate that urinary porphyrin concentrations relate quantitatively to DMPS-mobilizable mercury in the kidney and, therefore, serve as a biochemical measure of renal mercury content.

Examination of dietary methylmercury exposure in the Casa Pia Study of the health effects of dental amalgams in children.

This study examined methylmercury concentrations in blood of children participating in the Casa Pia Study of the Health Effects of Dental Amalgams in Children over a 1-yr period and related them to their diets in terms of fish and other seafood consumption. One hundred and fifty children between the ages of 8 and 10 yr who were residents of the Casa Pia School System of Lisbon, Portugal, participated. Parents or caregivers completed a food frequency questionnaire designed specifically for this study at baseline. Children provided urinary and blood samples for mercury determinations at baseline and at 1 yr following placement of dental tooth fillings. Mercury levels in fish samples from children's diets were also obtained. Mercury determinations in urine, blood, and fish were performed using cold vapor atomic fluorescence spectroscopy. The mean value of baseline methylmercury concentrations in blood increased as the report of seafood consumption increased, although not statistically significantly. However, blood methylmercury and total mercury concentrations were significantly lower at 1-yr follow-up than at baseline. Sixty-one percent of parents/caregivers reported that their children consumed fish on a weekly basis. The fish offered at a sample of the schools contained low levels of methylmercury (range 13.9-23.6 ng/g). Thus, children participating in the Casa Pia dental amalgam study are exposed to low dietary levels of methylmercury by way of fish consumption, and this finding was reflected in the low mean blood methylmercury concentrations observed. The present findings indicate that dietary methylmercury is not a significant source of mercury exposure and is not likely to confound the association of dental amalgam mercury with potential health effects in the present study.

HPLC methods for analysis of porphyrins in biological media.

Changes in porphyrin concentrations in biological media may serve as biological indicators of exposure and toxicity from a wide variety of drugs and chemical agents. This unit describes procedures for quantitative extraction of porphyrins from urine, feces, blood, and biological tissues as well as their separation and analysis by HAPLY spectrofluorometrc techniques.

Quantitative evaluation of heme biosynthetic pathway parameters as biomarkers of low-level lead exposure in rats.

Erythrocyte delta-aminolevulinic acid dehydratase (ALAD) activity, erythrocyte zinc protoporphyrin (ZPP)/heme ratio, and urinary coproporphyrin (UC) concentration have been employed as biological indicators of moderate-to high-level lead exposure, corresponding to blood levels in excess of 50 micrograms/dl, in human subjects. The comparative efficacy of these measures as indicators of lead exposure consistent with sustained lower blood lead levels has not been systematically evaluated. In the present studies, we examined the relative sensitivity and magnitude of response of these three bioindicators in rats during chronic exposure to 0, 100, or 1000 ppm lead as lead acetate in drinking water for up to 10 wk, followed by a 10-wk postexposure period, with weekly assessments, or during subchronic exposure to 0 or 1000 ppm lead as lead acetate in drinking water for 6 d, with daily assessments. Analysis of variance (ANOVA) was used to determine if the lead-treated rats differed from controls and to distinguish between dose groups with respect to the three biochemical indices of lead exposure. The data were normalized by conversion to Z scores in order to compare indicators with regard to magnitude of change in response to lead treatment. The order of sensitivity of each indicator was determined by considering the magnitude of the correlation coefficient (r) between the indicator and the blood lead concentration in each study. The indicators in order of decreasing sensitivity to lead in the chronic study were UC > ZPP/heme > ALAD. The indicators in order of decreasing magnitude of change in response to change in blood lead level were also UC > ZPP/heme > ALAD. None of the heme pathway parameters was judged a satisfactory substitute for direct blood lead measurement as an indicator of low-level lead exposure. However, urinary coproporphyrin appears most useful in this respect owing to highest sensitivity and magnitude of change relative to blood lead content and relatively low variation of mean coproporphyrin levels.