Validity of methyl mercury hair analysis: mercury monitoring in human scalp/nude mouse model

OBJECTIVE: The grafting of human scalp hair was used as a new application of this method to explore methyl mercury incorporation into human hair and to validate this model for mercury monitoring in hair. METHODS: Human scalp grafts were transplanted to athymic BALB/c nude mice. The animals were exposed to methyl mercury either as a single dose i.p. or continuously for 4 months, using ALZET osmotic pumps. The mercury concentration in hair was determined using x-ray fluorescence (XRF) spectrometry by segmental (2 mm) analysis of a single strand, and tissue concentrations were measured by cold vapor atomic absorption analysis. RESULTS: Human scalp hair grown in nude mice showed long-term persistence of human features including the expression of histocompatibility antigens (KAB 3, W 6/32, SF 1-1.1.1) and normal hair morphometry. The disposition of methyl mercury in nude mice followed a one-compartment model with a whole body elimination half-life of 6.7 days (elimination constant, k = 0.1/day). Autoradiographic studies revealed that methyl mercury was rapidly incorporated into areas of the hair follicle undergoing active keratinization. Methyl mercury concentrations in human hair transplanted onto nude mice were two orders of magnitude higher than in blood and attained a mean hair: blood ratio of 217 : 1, similar to ratios reported only in human studies. CONCLUSIONS: This study demonstrated that human hair grown on nude mice can record the level of exposure to methyl mercury and can serve as a valuable research tool to study mercury incorporation into human hair.     

A toxicokinetic model for predicting the tissue distribution and elimination of organic and inorganic mercury following exposure to methyl mercury in animals and humans. II. Application and validation of the model in humans

The objective of this study was to develop a biologically based dynamical model describing the disposition kinetics of methyl mercury and its inorganic mercury metabolites in humans following different methyl mercury exposure scenarios. The model conceptual and functional representation was similar to that used for rats but relevant data on humans served to determine the critical parameters of the kinetic behavior. It was found that the metabolic rate of methyl mercury was on average 3 to 3.5 times slower in humans than in rats. Also, excretion rates of organic mercury from the whole body into feces and hair were 100 and 40 times smaller in humans, respectively, and urinary excretion of organic mercury in humans was found to be negligible. The human transfer rate of inorganic mercury from blood to hair was found to be 5 times lower than that of rats. On the other hand, retention of inorganic mercury in the kidney appeared more important in humans than in rats: the transfer rate of inorganic mercury from blood to kidney was 19 times higher than in rats and that from kidney to blood 19 times smaller. The excretion rate of inorganic mercury from the kidney to urine in humans was found to be twice that of rats. With these model parameters, simulations accurately predicted human kinetic data available in the published literature for different exposure scenarios. The model relates quantitatively mercury species in biological matrices (blood, hair, and urine) to the absorbed dose and tissue burden at any point in time. Thus, accessible measurements on these matrices allow inferences of past, present, and future burdens. This could prove to be a useful tool in assessing the health risks associated with various circumstances of methyl mercury exposure.     

Methyl mercuric chloride toxicokinetics in mice. II: Sexual differences in whole-body retention and deposition in blood, hair, skin, muscles and fat

This article reports the time course for deposition of methyl mercury administered as a single oral dose in whole body, total carcass, liver, kidneys, brain, blood, fat, muscle, bone, skin and hair of male and female Bom:NMRI mice. The whole-body elimination initially approximated first order kinetics with half-times around 7 days and 12 days for males and females respectively, although a decreased elimination rate was observed during the last 10 days. The elimination of mercury from carcass was slower than the elimination from the whole-body, causing an increasing relative carcass deposition with time in both male and female mice and explaining the observed deviation from first order elimination kinetics. Thus, first order kinetics is observed only during 2-3 weeks after dosage. Throughout the experimental period, male mice had significantly lower levels of mercury in both blood, brain and muscles than had female mice, whereas renal deposition of mercury in male mice was significantly higher than in female mice. At day 30 the females had about twice as much mercury in liver, brain and hair (median values) as had male mice. Despite the fact that comparable whole-body retention and carcass deposition were observed in male and female mice, the blood concentrations in male mice was only about half that in female mice. Furthermore, half-times for mercury in blood did not differ much between male and female mice and were close to whole-body half-time in male mice, although the absolute amounts of mercury in both blood and whole-blood at day 20 were significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacodynamics of methyl mercury in the rainbow trout (Salmo gairdneri): tissue uptake, distribution and excretion

The tissue distribution, rate of uptake and concentration of ²⁰³Hg-labeled methylmercury was investigated in 20 different tissues/organs over a period of 100 days following a single intragastric dose of 0.5 mg Hg/kg body weight. Mercury content was analyzed by gamma scintillation spectrometry. After 1 hr, mercury concentration factors >0.1 were detected in the blood, heart, liver, spleen and kidney (a concentration factor (CF) of 1.0 equals mercury concentration in dose). Highest mercury concentrations (CF > 7.0) were observed in the blood (at 7 days) and spleen (at 14 days). After 100 days, the CF of the blood was >2.0 and the CF values of the spleen, kidney and liver were >1.0. Maximum CF values were reached in the skeletal muscle, brain and lens after 34, 56 and >90 days, respectively. Maximum values were reached in most other tissues/organs at approximately 7 days. Skeletal muscle appeared to function as a reservoir for methyl mercury and accumulated 50% of the dose from 34 to 100 days post administration. Methyl mercury accumulation in the brain was limited to 0.1% of the dose. The rate of mercury excretion appeared to be biphasic as a result of a slow elimination from the skeletal muscle relative to the other tissues/organs. Employing both the slow and fast rate, the half-retention time for methyl mercury in rainbow trout was estimated to be >200 days.     

Thimerosal distribution and metabolism in neonatal mice: comparison with methyl mercury

Thimerosal, which releases the ethyl mercury radical as the active species, has been used as a preservative in many currently marketed vaccines throughout the world. Because of concerns that its toxicity could be similar to that of methyl mercury, it is no longer incorporated in many vaccines in the United States. There are reasons to believe, however, that the disposition and toxicity of ethyl mercury compounds, including thimerosal, may differ substantially from those of the methyl form. The current study sought to compare, in neonatal mice, the tissue concentrations, disposition and metabolism of thimerosal with that of methyl mercury. ICR mice were given single intramuscular injections of thimerosal or methyl mercury (1.4 mg Hg kg(-1)) on postnatal day 10 (PND 10). Tissue samples were collected daily on PND 11-14. Most analysed tissues demonstrated different patterns of tissue distribution and a different rate of mercury decomposition. The mean organic mercury in the brain and kidneys was significantly lower in mice treated with thimerosal than in the methyl mercury-treated group. In the brain, thimerosal-exposed mice showed a steady decrease of organic mercury levels following the initial peak, whereas in the methyl mercury-exposed mice, concentrations peaked on day 2 after exposure. In the kidneys, thimerosal-exposed mice retained significantly higher inorganic mercury levels than methyl mercury-treated mice. In the liver both organic and inorganic mercury concentrations were significantly higher in thimerosal-exposed mice than in the methyl mercury group. Ethyl mercury was incorporated into growing hair in a similar manner to methyl mercury. The data showing significant kinetic differences in tissue distribution and metabolism of mercury species challenge the assumption that ethyl mercury is toxicologically identical to methyl mercury.     

Impact of consumption of freshwater fish on mercury levels in hair, blood, urine, and alveolar air

Human exposure to methylmercury occurs mainly via consumption of fish. The aim of the study was to investigate the influence of freshwater fish consumption on mercury levels in hair, blood, urine, and end-exhaled air. Twenty subjects without dental amalgam fillings were recruited from sport-fishing societies. They ranged in age from 61 to 87 yr. Six individuals ate freshwater fish at least once a week and were categorized as high consumers. Eight individuals were classified as medium consumers and ate freshwater fish at least once a month but less than once a week. Six individuals were categorized as low consumers and had not eaten freshwater fish in the past 3 mo. Among the high consumers, median concentrations of mercury were 8.6 microg/L in blood, 2.4 microg/g in hair, 10 pg/L in end-exhaled air, and 1.1 microg/g creatinine in urine. The relationship between freshwater fish consumption and mercury was significant in all biological media. The high-consumption group had much higher mercury levels in blood (9-fold), hair (7-fold), alveolar air (3-fold), and urine (15-fold) than the low-consumption group. The latter finding may be explained by demethylation of methylmercury in the body. The ratio between mercury concentration in blood and hair was 1:270. This implies that the typical blood-hair ratio of 1:250, specified by the World Health Organization (WHO) in 1990, is valid also for exposure to low amounts of methylmercury.     

Toxicokinetics of methyl mercury in pigs

Toxicokinetics of methyl mercury were studied in pigs after intravenous (i.v.) administration of the compound. The distribution of methyl mercury was slow taking 3–4 days to be completed. Blood elimination half-life was found to be 25 days. The apparent volume of distribution was 9.8 l/kg indicating pronounced tissue accumulation of methyl mercury. Highest mercury levels were found in kidney and liver, with lower contents in muscle and brain and very little in adipose tissue. The results indicate that from organs like liver and kidney methyl mercury is eliminated much more slowly than from the blood. Over a period of 15 days 16% of the dose administered was excreted with faeces and 0.9% in the urine.     

Mercury, pets’ and hair: baseline survey of a priority environmental pollutant using a noninvasive matrix in man’s best friend

Pet cats and dogs have been successfully used as indicators of environmental pollution by a great variety of chemicals, including metals. However, information on mercury (a well know priority environmental pollutant) concentrations in household pets tissues and/or organs is scarce. Thus, in the present work we quantified total mercury (Hg_Total) in blood and hair samples from twenty-six household dogs. The obtained results disclose relatively low levels of total mercury in the surveyed dogs, with values ranging from 0.16 to 12.38 ng g^?1 in blood; and from 24.16 to 826.30 ng g^?1 in hair. Mercury concentrations were independent of gender, age and diet type. A highly significant positive correlation was established between total mercury in blood and hair, validating the latter as a surrogate, non-invasive matrix for mercury exposure evaluation. Additionally, the obtained blood to hair ratio (200) is similar to the one described for humans reinforcing the suitability of dogs as sentinels. Overall, the determination of total mercury levels in dogs’ hair samples proved to be a good screening method for the estimation of mercury burden in this species. We propose the quantification of Hg_Total in hair as a screening method for sentinels like household pets to be performed in routine veterinary visits.     

Distribution of mercury in rabbits subchronically exposed to low levels of radiolabeled methyl mercury

The metabolism of methyl mercury (MeHg) has been studied in rabbits administered 203Hg-labeled methyl mercuric chloride, 0.125 mumol/kg body weight, twice a week for 9 weeks, by intravenous injection. Twelve weeks after cessation of treatment, about 54% of the administered dose had been excreted in faeces and 5% in urine. After one week, the highest concentration of 203Hg was found in fur (8.6 nmol Hg/g). Substantially lower concentrations were found in kidney (2.5 nmol/g), liver (0.9 nmol/g), brain (0.4 nmol/g), muscle (0.3 nmol/g) and blood (0.1 nmol/g). The rate of elimination of 203Hg from brain, muscle and blood was faster (t1/2 about 12 days) than that from kidney and liver (t1/2 about 28 days). The relative amount of inorganic Hg in kidney and liver increased with time after cessation of treatment. The highest fractions were 85 and 70%, respectively. In brain, no significant demethylation of MeHg could be detected.     

The effect of weaning on blood, hair, fecal and urinary mercury after chronic ingestion of methylmercuric chloride by infant monkeys

Several studies suggest that infant animals may be more sensitive to toxic insult from methylmercury than adults. In our experiment, newly born infant monkeys were given equivalent daily doses of 50 micrograms Hg/kg body weight orally in the form of methylmercury for more than 60 weeks. Data revealed that after weaning at 200 days, both blood and hair mercury showed a sudden drop which was accompanied by an increase in fecal mercury excretion.     

Evaluation of mercury in hair,blood and muscle as biomarkers for methylmercury exposure in male and female mice

Recently established reference intervals demonstrate that blood mercury is significantly higher in women than in men. Mercury in blood and hair are both used as biomarkers for human methylmercury exposure and employed in risk assessment without considering possible sex-related differences in toxicokinetics of methylmercury. In an experimental study using male and female mice of three different strains, the validty of mercury in hair, blood and muscle as indicators of methylmercury exposure was evaluated. Significant sex-related differences in the toxicokinetics of methylmercury were observed in the mice and it is concluded that hair and blood levels of mercury are of questionable relevance as indicators of both body burden and target organ concentrations of mercury. However, blood concentrations might be used as an indicator of brain deposition and the correlation improves after corrections due to sex-related differences in toxicokinetics.     

Glutathione enzyme and selenoprotein polymorphisms associate with mercury biomarker levels in Michigan dental professionals

Mercury is a potent toxicant of concern to both the general public and occupationally exposed workers (e.g., dentists). Recent studies suggest that several genes mediating the toxicokinetics of mercury are polymorphic in humans and may influence inter-individual variability in mercury accumulation. This work hypothesizes that polymorphisms in key glutathione synthesizing enzyme, glutathione s-transferase, and selenoprotein genes underlie inter-individual differences in mercury body burden as assessed by analytical mercury measurement in urine and hair, biomarkers of elemental mercury and methylmercury, respectively. Urine and hair samples were collected from a population of dental professionals (n = 515), and total mercury content was measured. Average urine (1.06 ± 1.24 ug/L) and hair mercury levels (0.49 ± 0.63 ug/g) were similar to national U.S. population averages. Taqman assays were used to genotype DNA from buccal swab samples at 15 polymorphic sites in genes implicated in mercury metabolism. Linear regression modeling assessed the ability of polymorphisms to modify the relationship between mercury biomarker levels and exposure sources (e.g., amalgams, fish consumption). Five polymorphisms were significantly associated with urine mercury levels (GSTT1 deletion), hair mercury levels (GSTP1-105, GSTP1-114, GSS 5′), or both (SEPP1 3′UTR). Overall, this study suggests that polymorphisms in selenoproteins and glutathione-related genes may influence elimination of mercury in the urine and hair or mercury retention following exposures to elemental mercury (via dental amalgams) and methylmercury (via fish consumption).     

A toxicokinetic model for predicting the tissue distribution and elimination of organic and inorganic mercury following exposure to methyl mercury in animals and humans. I. Development and validation of the model using experimental data in rats

The objective of this study was to develop a biologically based dynamic model for predicting the distribution and elimination of methyl mercury and its metabolite, inorganic mercury, under a variety of exposure scenarios in rats. A model is proposed based on a multicompartment approach; each compartment represents an organ or a group of organs or an excreta. The model translates into a set of coupled differential equations taking into account interorgan rates of exchanges and excretion together with the biotransformation process. The free parameters of the model are determined from statistical fits to the experimental data of the Farris et al. (Toxicol. Appl. Pharmacol. 119, 74-90, 1993) study on the time profiles of blood and tissue concentrations and cumulative excretions. The vast range of time scales that govern tissue absorption, distribution, biotransformation, and excretion served to solve the model step by step. This interplay of time scales in the rates explains the buildups and slow attrition of inorganic mercury in certain key organs such as the brain and the kidney, which are also the sites of the more important toxic effects. The model was validated on additional experimental data provided by Norseth and Clarkson (Arch. Environ. Health 21, 717-727, 1970) and Thomas et al. (Environ. Res. 41, 219-234, 1986; Environ. Res. 43, 203-216, 1987). This approach, when adapted to humans, allows the reconstruction of the time course of blood and tissue concentrations, starting from easily accessible data on hair, urine, and feces.     

Indices of mercury contamination during breast feeding in the Amazon Basin

Mercury pollution, due to gold mining has spread through the Amazon ecosystem reaching the food chain and affecting the indigenous people of the region. We studied the mercury contamination of 47 mothers and infants and the role of breast feeding in indices of mercury body burden in both groups, by measuring hair and milk Hg levels. Total mercury concentration of breast milk ranged from 0.0 to 24.8 (5.85, 5.2 S.D.) ng/g. Calculated levels of mercury exposure of breast fed babies indicated that 53% were above tolerable daily intakes (0.5 μg/kg body weight) recommended for adults by WHO. Mercury concentration in maternal hair was higher than in hair from breast-fed babies. Correlation analysis showed that mercury hair concentration in infants was significantly affected by maternal mercury contamination during pregnancy, but not during the post-natal breast-feeding period. The mercury concentration in milk was not significantly correlated with maternal or infant's hair Hg. A statistically significant correlation was found only between maternal and infant's hair mercury concentration (r=0.675; P=0.0001).     

Hair-to-blood ratio and biological half-life of mercury: experimental study of methylmercury exposure through fish consumption in humans

The hair-to-blood ratio and biological half-life of methylmercury in a one-compartment model seem to differ between past and recent studies. To reevaluate them, 27 healthy volunteers were exposed to methylmercury at the provisional tolerable weekly intake (3.4 μg/kg body weight/week) for adults through fish consumption for 14 weeks, followed by a 15-week washout period after the cessation of exposure. Blood was collected every 1 or 2 weeks, and hair was cut every 4 weeks. Total mercury (T-Hg) concentrations were analyzed in blood and hair. The T-Hg levels of blood and hair changed with time (p < 0.001). The mean concentrations increased from 6.7 ng/g at week 0 to 26.9 ng/g at week 14 in blood, and from 2.3 to 8.8 μg/g in hair. The mean hair-to-blood ratio after the adjustment for the time lag from blood to hair was 344 ± 54 (S.D.) for the entire period. The half-lives of T-Hg were calculated from raw data to be 94 ± 23 days for blood and 102 ± 31 days for hair, but the half-lives recalculated after subtracting the background levels from the raw data were 57 ± 18 and 64 ± 22 days, respectively. In conclusion, the hair-to-blood ratio of methylmercury, based on past studies, appears to be underestimated in light of recent studies. The crude half-life may be preferred rather than the recalculated one because of the practicability and uncertainties of the background level, though the latter half-life may approximate the conventional one.     

Comments on the Article “The Toxicology of Mercury and Its Chemical Compounds” by Clarkson and Magos (2006)

provide their perspectives on the toxicology of mercury vapor and dental amalgam. As scientists who are involved in preparing a German federal guidline regarding dental amalgam, we welcome additional scientific data on this issue. However, Clarkson and Magos do not present all the relevant studies in their review. The additional data provided here show that: (a) Dental amalgam is the main source of human total mercury body burden, because individuals with amalgam have 2–12 times more mercury in their body tissues compared to individuals without amalgam; (b) there is not necessarily a correlation between mercury levels in blood, urine, or hair and in body tissues, and none of the parameters correlate with severity of symptoms; (c) the half-life of mercury deposits in brain and bone tissues could last from several years to decades, and thus mercury accumulates over time of exposure; (d) mercury, in particular mercury vapor, is known to be the most toxic nonradioactive element, and is toxic even in very low doses, and (e) some studies which conclude that amalgam fillings are safe for human beings have important methodogical flaws. Therefore, they have no value for assessing the safety of amalgam.     

Toxicokinetic interactions and survival of Hyalella azteca exposed to binary mixtures of chlorpyrifos, dieldrin, and methyl mercury

Chemical mixture interactions of chlorpyrifos, dieldrin, and methyl mercury were evaluated in Hyalella azteca. Survival of adult and juvenile organisms was evaluated following exposure to individual chemicals and in binary combinations. Binary interactions of the model chemicals on survival of adult and juvenile H. azteca were evaluated by concentration-response curve analysis as additive, synergistic, antagonistic, or independent. Chlorpyrifos and methyl mercury interacted additively, while dieldrin interacted independently with both chlorpyrifos and methyl mercury. Toxicodynamic interactions were evaluated by measuring accumulation and elimination of each model toxicant in the presence of a second toxicant. Chlorpyrifos significantly increased the amount of methyl mercury accumulated in the first 12 h of exposure. Dieldrin did not interact with chlorpyrifos or methyl mercury in the accumulation or elimination experiments. Accumulation of chlorpyrifos was not observed. Results of the current investigation demonstrate that chlorpyrifos and methyl mercury interact additively, which would otherwise be predicted to act independently.     

Comments on the article "the toxicology of mercury and its chemical compounds" by Clarkson and Magos (2006)

Clarkson and Magos (2006) provide their perspectives on the toxicology of mercury vapor and dental amalgam. As scientists who are involved in preparing a German federal guideline regarding dental amalgam, we welcome additional scientific data on this issue. However, Clarkson and Magos do not present all the relevant studies in their review. The additional data provided here show that: (a) Dental amalgam is the main source of human total mercury body burden, because individuals with amalgam have 2-12 times more mercury in their body tissues compared to individuals without amalgam; (b) there is not necessarily a correlation between mercury levels in blood, urine, or hair and in body tissues, and none of the parameters correlate with severity of symptoms; (c) the half-life of mercury deposits in brain and bone tissues could last from several years to decades, and thus mercury accumulates over time of exposure; (d) mercury, in particular mercury vapor, is known to be the most toxic nonradioactive element, and is toxic even in very low doses, and (e) some studies which conclude that amalgam fillings are safe for human beings have important methodogical flaws. Therefore, they have no value for assessing the safety of amalgam.     

Comparison of the effect of N-(2,3-dimercaptopropyl) phthalamidic acid, dl-penicillamine,and dimercaprol on the excretion of tissue retention of mercury in mice

The effect of N-(2,3-dimercaptopropyl) phthalamidic acid (DMPA) on the elimination and tissue retention of mercury was investigated on male ddY mice and was compared with those of dimercaprol (BAL) and dl-penicillamine (dl-p). When 75 mg/kg (about a quarter of an LD50) of DMPA and HgCl₂ (0.5 mg Hg/kg) were injected subcutaneously at almost the same time for 5 days, a decrease of the mercury concentration in vital organs and blood and an increase in urinary and fecal elimination of mercury were noted. These effects were greater than those caused by BAL (25 mg/kg) and dl-p (50 mg/kg) injections. DMPA injected after the discontinuation of HgCl₂ dramatically increased the fecal excretion of mercury and inhibited its retention in tissues more effectively than did BAL and dl-p. Approximately the same results were obtained in an experiment using equimolar doses (55 mg/kg for DMPA, 25 mg/kg for BAL, or 30 mg/kg for dl-p) of these compounds. The mechanism involved in the action of DMPA on fecal excretion of mercury was also investigated. DMPA (75 mg/kg) and BAL (25 mg/kg) enhanced the bile flow rate and mercury excretion into bile, the effect of DMPA on the latter being 15% of the body burden and that of BAL, 5.4%, dl-p (50 mg/kg) had no appreciable effect on this. The thiol compounds did not immediately induce the absorption of mercury in bile from the small intestine, but 2 hr later about 8% of the mercury was absorbed in the DMPA group only. The compounds increased slightly the intestinal transit of mercury. An increase of mercury in feces after the injection of DMPA was thus concluded to be due to an increase in biliary excretion.     

吴江地区新生儿脐血汞与胎发汞含量的分析与评价

目的:评价吴江地区新生儿宫内汞暴露情况及疫苗接种后血汞的变化.方法:选择2009～2010年在吴江市第一人民医院出生的新生儿102例,作脐血汞和胎发汞含量测定,其中38例入住新生儿科病房者,出生时已接种乙肝疫苗,在出生第5d时做血汞测定.结果:102例新生儿脐血汞平均值为(2.96±1.20) μg/kg,胎发汞平均值为(281.77±113.17) μg/kg,两者呈正相关(r=0.452,P＜0.05);38例已接种乙肝疫苗新生儿脐血汞平均值为(2.86±1.57) μg/kg,胎发汞平均值为(279.71±135.79) μg/kg,两者之间呈显著正相关(r=0.486,P＜0.05).38例已接种乙肝疫苗新生儿出生第5d血汞平均值为(3.06±1.61) μg/kg,与出生时脐血汞比较差异无统计学意义(t=0.55,P＞0.05).结论:吴江地区尚未发现地区性的汞污染.新生儿脐血汞与胎发汞均能比较准确地反映胎儿宫内汞暴露情况,可取其中一项标本检测.新生儿接种乙肝疫苗后血汞水平无显著升高.