Invited Review Article
The retention time of inorganic mercury in the brain — A systematic review of the evidence

https://doi.org/10.1016/j.taap.2013.12.011Get rights and content

Abstract

Reports from human case studies indicate a half-life for inorganic mercury in the brain in the order of years—contradicting older radioisotope studies that estimated half-lives in the order of weeks to months in duration. This study systematically reviews available evidence on the retention time of inorganic mercury in humans and primates to better understand this conflicting evidence. A broad search strategy was used to capture 16,539 abstracts on the Pubmed database. Abstracts were screened to include only study types containing relevant information. 131 studies of interest were identified. Only 1 primate study made a numeric estimate for the half-life of inorganic mercury (227–540 days). Eighteen human mercury poisoning cases were followed up long term including autopsy. Brain inorganic mercury concentrations at death were consistent with a half-life of several years or longer. 5 radionucleotide studies were found, one of which estimated head half-life (21 days). This estimate has sometimes been misinterpreted to be equivalent to brain half-life—which ignores several confounding factors including limited radioactive half-life and radioactive decay from surrounding tissues including circulating blood. No autopsy cohort study estimated a half-life for inorganic mercury, although some noted bioaccumulation of brain mercury with age. Modelling studies provided some extreme estimates (69 days vs 22 years). Estimates from modelling studies appear sensitive to model assumptions, however predications based on a long half-life (27.4 years) are consistent with autopsy findings. In summary, shorter estimates of half-life are not supported by evidence from animal studies, human case studies, or modelling studies based on appropriate assumptions. Evidence from such studies point to a half-life of inorganic mercury in human brains of several years to several decades. This finding carries important implications for pharmcokinetic modelling of mercury and potentially for the regulatory toxicology of mercury.

Introduction

The concept of elimination half-life is fundamental to the study of pharmacokinetics and toxicokinetics. The half-life for a xenobiotic is defined as the time taken for the xenobiotic to decrease its concentration in a given body compartment by 50% and this relationship is observed to hold true for a given xenobiotic provided the assumption of first order kinetics is valid (Flomenbaum et al., 2006). Additionally, a steady state concentration is arrived at after a time of approximately 5 times the elimination half-life for a given xenobiotic (assuming first order kinetics)—the ultimate concentration reached depending on the elimination half-life, the rate of exposure and the volume of distribution for the particular xenobiotic (Flomenbaum et al., 2006). It follows that given a longer half-life, the phenomenon of bioaccumulation may be observed—i.e. the slow increase in tissue levels of a xenobiotic with time at constant exposure—even at very low exposure levels.

Consideration of these concepts allows for modelling and analysis that can be used to address important practical issues, such as maximum safe daily exposure levels for a given toxic substance. For example, using such considerations Takeuchi et al. made use of estimations of the half-life of methyl-mercury in combination with clinical observations of toxicity in Minamata Disease patients to calculate a maximum safe permissible daily intake of methyl-mercury (Takeuchi et al., 1970) (N.B. A recent follow up of Niigata Minamata Disease patients has found evidence of toxic effects at exposure levels lower than had previously been realised (Maruyama et al., 2012)). Turning our attention to inorganic mercury, it is striking that the half-life of inorganic mercury in the brain remains an undefined quantity. Inorganic mercury itself cannot access the brain, however as elemental mercury, ethyl-mercury and methyl-mercury are all metabolised to inorganic mercury within the brain (Burbacher et al., 2005, Dórea et al., 2013, Vahter et al., 1994), knowledge of its half-life is important in the modelling of the toxicity of all forms of mercury in humans.

It is thought that the long-term storage form of inorganic mercury in the brain is mercury-selenide (Björkman et al., 1995, Clarkson and Magos, 2006, Falnoga and Tusek-Znidaric, 2007, Kosta et al., 1975, Nylander and Weiner, 1991). Based on observations in occupationally exposed cohorts (Falnoga and Tusek-Znidaric, 2007), and a very low solubility product of mercury selenide (Ks = 10 58) (Clarkson and Magos, 2006, WHO, 1990), it has been assumed that mercury-selenide deposits in the brain are chemically inert and non-toxic. However studies in monkeys have found that persistent inorganic mercury in the brain was associated with increased count of inflammatory cells (microglia) and decreased count of astrocytes (Burbacher et al., 2005, Charleston et al., 1994, Charleston et al., 1995, Vahter et al., 1994, Vahter et al., 1995). More recently a study by Korbas et al. found evidence that mercury-selenide may not be the only form of mercury present in people exposed to methyl-mercury over different doses and timescales (Korbas et al., 2010). Our understanding of mercuric-selenide in the human brain is therefore evolving, however this is beyond the scope of the current paper, which aims to focus on the half-life of inorganic mercury in the brain from a pharmacokinetic perspective.

Perilously few studies on the half-life of inorganic mercury in the human brain exist. However in the past a number of studies were carried out using radioisotopes—that is administration of small quantities of radioactive 197Hg & 203Hg to volunteers and measurement of the radiation emitted by various body parts over a follow up time (Hattula and Rahola, 1975, Hursh et al., 1976, Rahola et al., 1973). The study by Hursh and colleagues led to an estimate of the half-life of inhaled mercury in the head of 21 days (Hursh et al., 1976), and based upon Hursh's paper the figure of 20 days remains listed as the half-life of inorganic mercury in the brain in Table 2.4 of the influential ATSDR toxicological profile for mercury (ATSDR, 1999) (This figure is again cited in Appendix A of the profile as supporting evidence for calculated minimum risk levels (MRL's) for exposure to mercury vapour (ATSDR, 1999.)). Such low figures for the brain half-life are in sharp contrast to evidence from primate studies (Vahter et al., 1995), findings in known cases of mercury poisoning followed up over the very long term, and estimates from some kinetics modelling studies (Sugita, 1978). Numerous cases of both elemental mercury exposure and organic mercury exposure have been followed up long term, and on autopsy many years after exposure significant levels of inorganic mercury have been found in the brain (Davis et al., 1994, Eto et al., 1999, Hargreaves et al., 1988, Kosta et al., 1975, Opitz et al., 1996, Takeuchi et al., 1989). Assuming first order kinetics, these results imply a half-life in the brain of years in duration. However as we often cannot accurately determine initial dose it is not possible to calculate a value for the half-life from individual cases. The absence of an agreed figure for the half-life has led to a lack of appreciation amongst some authors for the extremely long retention time of mercury in the brain: “Studies with radioactive tracers indicate that the rate of overall excretion of mercury from the body can be described by a single half-time of about 58 days, corresponding to an excretion rate of slightly more than 1% of the body burden per day. Most tissues have the same or shorter half-times.” (Clarkson, 2002).

Such uncertainty surrounding the half-life of inorganic mercury in the human brain is clearly problematic. Therefore this work was undertaken with the aim to perform a systematic review of the mercury literature to identify all available evidence in both primates and humans that could be used to make analytic inferences about the half-life of inorganic mercury in the brain.

The search was limited to human and animal studies because “observed inter- and intraspecies differences in the type and severity of the toxic response to mercury may result from differences in the absorption, distribution, transformation, and end tissue concentration of the parent mercury compound.” (ATSDR, 1999). Such differences are likely to lead to differences in estimates of brain half-life between species. Initial search strategies using descriptive terms such as “brain” “half-life” and” mercury” failed to provide useful results. For this reason it was decided to use a very broad search strategy to capture as many papers with relevant information as possible. The Pubmed database was searched (last search update on 23/04/2013) using MESH terms pertaining to mercury toxicity (Fig. 1).

This led to a very large number of hits N = 16,539. The search was restricted to English language papers on humans or mammals whose title or abstract mentioned mercury in the brain, organ measurements of mercury, autopsy studies and mercury case studies, or half-life. Review papers and studies examining samples from foetuses and children were excluded as pharmacokinetics may differ in the very young. This left 984 papers of potential interest. After a second round of screening the remaining papers were categorised by species — human or primate. A limited number of additional papers not captured by the search but known by the author were also included. The full reprint of all remaining papers was then obtained where possible and reviewed. Reprints of 7 papers could not be obtained: Ando et al., 1985 — a tissue study; Carrel et al., 1979 —a cohort exposure study; Cheung and Verity, 1983 — an experimental exposure study; Fair et al., 1986 — an experimental exposure study; Kozik, 1978 — an autopsy study; Newton and Fry, 1978 — report of accidental exposure; Murai et al., 1982 — primate experimental study).

The search strategy and numbers of papers found are summarised in the flow diagram in Fig. 1.

Primate studies were reviewed to identify papers that provided direct estimates of the mercury half-life. Effectively this meant that papers included were those where primates were exposed to some form of mercury, allowed to survive for some period of time post exposure, and at sacrifice had autopsy with measurement of inorganic mercury levels in brain tissue. The analysis strategy and results for those studies that determined the retention half-life for inorganic mercury during analysis were summarised.

Modelling studies that were captured by the search strategy were identified and examined for calculations of the brain half-life. These studies were summarised in tabular form detailing modelling approach, important assumptions, and half-life findings if present.

Human case reports where one or more persons were exposed to mercury and followed up over a prolonged period before death, and where subsequent autopsy including measurement of tissue levels of mercury, were identified. These studies could not be used to calculate a precise half-life for mercury in the brain for each case, however assuming first order kinetics (implying near complete elimination of inorganic mercury after 5 half-lives), presence or absence of elevated levels of inorganic mercury at autopsy would allow the calculation of a minimum or maximum bound for half-life. Only cases with follow up post mercury exposure of one year or greater were used to estimate bounds.

Autopsy studies with N > 15 and where brain Hg levels were measured were summarised in tabular form. These studies are potentially useful in determining half-life as results from autopsy studies can be used to determine organ half-life using kinetics modelling approaches (Sugita, 1978). Any studies that calculated a half-life for inorganic mercury in the brain were identified. These studies were also of interest as analysis of trends of bioaccumulation of mercury in the brain over time amongst populations with relatively uniform mercury exposure may be informative regarding half-life. This is based on the observation that, assuming first order kinetics at a steady state exposure, the end organ concentration will reach a steady state in approximately 5 half-lives for a given exogenous substance (Flomenbaum et al., 2006). Assuming that the exposure over time remains relatively constant, this allows us to make predictions of what the relationship between age and brain inorganic mercury levels might look like given different half-lives.

However, in attempting to utilise such an approach to measure the half-life of mercury in humans, we must recognise the dangers of unmeasured confounders, idiosyncratic kinetics in individuals and population subgroups with altered toxicokinetics (for example — carriage of GCLM-588T allele has been associated with elevated levels of blood, plasma and urine total mercury (Custodio et al., 2005)). Nevertheless examination of autopsy studies may provide insight regarding bioaccumulation.

Section snippets

Primate studies

Of the 42 primate research papers identified, only five studies provided estimates or made inferences about the half-life of inorganic mercury in the brain. Table 1 displays a summary of the critical factors of these studies including exposure type, follow up time and estimated inorganic mercury brain half-life. Note that not all papers measured inorganic mercury and two studies are based on the same experimental animals. Of the five studies only one study made numeric estimates of the brain

Discussion

Despite a broad and extensive search strategy this review has identified only a handful of studies providing evidence on the retention time of inorganic mercury in the primate and human brain. Whilst several studies have noted the half life to be very long, only one animal study and two modelling studies put figures on a half-life estimate specifically for inorganic mercury, with Vahter et al. (1995) arriving at a figure of 227–540 days (0.62–1.48 years) in M. fascicularis monkeys, and with the

Conflict of interest statement

I have no conflicts of interest to declare.

Acknowledgments

I would like to acknowledge Professor Jose Dorea, Faculty of Health Sciences, Universidade de Brasilia, Brazil, for providing support and critical feedback. I would also like to acknowledge Professor Kevin Nolan, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland for his support.

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