Next Article in Journal
Evaluation of Chronic Disease Prevention and Control Public Service Advertisement on the Awareness and Attitude Change among Urban Population in Chongqing, China: A Cross-Sectional Study
Previous Article in Journal
Gaming Device Usage Patterns Predict Internet Gaming Disorder: Comparison across Different Gaming Device Usage Patterns
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Metal Neurotoxins: An Important Role in Current Human Neural Epidemics?

Materials Research Laboratory, University of California Santa Barbara, Santa Barbara, CA 93106-5121, USA
Int. J. Environ. Res. Public Health 2017, 14(12), 1511; https://doi.org/10.3390/ijerph14121511
Submission received: 20 October 2017 / Revised: 29 November 2017 / Accepted: 30 November 2017 / Published: 5 December 2017
(This article belongs to the Section Environmental Health)

Abstract

:
Many published studies have illustrated that several of the present day neurological epidemics (autism, attention deficit disorder, Alzheimer’s) cannot be correlated to any single neurotoxicant. However, the present scientific examination of the numerous global blood monitoring databases for adults that include the concentrations of the neurotoxic elements, aluminum (Al), arsenic (As), lead (Pb), manganese (Mn), mercury (Hg), and selenium (Se) clearly indicate that, when considered in combination, for some, the human body may become easily over-burdened. This can be explained by changes in modern lifestyles. Similar data, solely for pregnant women, have been examined confirming this. All these elements are seen to be present in the human body and at not insignificant magnitudes. Currently suggested minimum risk levels (MRL) for humans are discussed and listed together with averages of the reported distributions, together with their spread and maximum values. One observation is that many distributions for pregnant women are not too dissimilar from those of general populations. Women obviously have their individual baseline of neurotoxin values before pregnancy and any efforts to modify this to any significant degree is not yet clearly apparent. For any element, distribution shapes are reasonably similar showing broad distributions with extended tails with numerous outlier values. There are a certain fraction of people that lie well above the MRL values and may be at risk, especially if genetically susceptible. Additionally, synergistic effects between neurotoxins and with other trace metals are now also being reported. It appears prudent for women of child-bearing age to establish their baseline values well before pregnancy. Those at risk then can be better identified. Adequate instrumental testing now is commercially available for this. In addition, directives are necessary for vaccination programs to use only non-neurotoxic adjuvants, especially for young children and all women of child-bearing ages. Additionally, clearer directives concerning fish consumption must now be reappraised.

1. Introduction

The risks associated with neurotoxicant materials have been with us from the age of chemical discovery and particularly through their usage in the colonial and industrial revolution periods. Gold and silver mining casualties, “mad as a hatter” cases, and the Japanese Minamata Bay pollution, all a result of mercury, are historically documented examples [1,2], as well as the possible role for lead in the fall of the Roman Empire. However, these were generally in specific geographic regions or related to industrial consequences. Now, global neurological illnesses that are widespread and cover general populations are becoming increasingly evident in epidemic numbers especially in young children and in the aged, and appear to result from anthropogenic environmental causes undoubtedly coupled to genetic susceptibilities [3,4]. Autism in children affects male/female babies in a ratio of roughly four to one, possibly indicating an additional role of hormones. Overall, its rate of occurrence has increased in the recent period of 30 years by several orders of magnitude. In US births, within the first two years of life, its present rate is at levels of one in eighty births or even more so, and high rates are also of global concern [5,6]. Attention Deficit Hyperactivity Disorder (ADHD) in children has also rapidly grown in recent decades [7]. Alzheimer’s disease has also become globally widespread and is listed as a growing epidemic [8]. Most recently, copper and iron have been suggested as being possibly involved, but this remains speculative due to the fact that these are not known as neurotoxins [9,10]. However, as will be noted, such metals may enhance the effects of some neurotoxicants. In a recent paper involving the Indian population, suggestions center on potential risks from mercury from coal combustion coupled to mercury in marine food products, which is quite plausible [11]. A “dementia epidemic” has also been suggested as being largely under-recognized and in need of concern [12]. Although psychiatric diagnostic abilities certainly have improved and widened the boundaries for most neurological illnesses, the ever drastic changes seen do reflect real growth, yet suggested causes remain unproven and generally remain speculative and not widely accepted.
One major difference from the past is that significant monitoring capability now exists particularly for chemicals in the body, and there is an increased acceptance and sensitivity to potential environmental contributions and hazards. Moreover, there is a recognition that neurotoxicant materials are present in the human environment and increasing in quantity in some cases through modern lifestyles. Technically, it should, therefore, now be easier in theory to recognize, minimize, and potentially control such risks. In the early 1960s the medical profession became shocked by the effect on some pregnancies of the organic pharmaceutical-chemical thalidomide [13]. Mainly prescribed in Europe, where this was first synthesized, deformed babies were born missing limbs or with other defects. Its causal identity was soon realized and its use banned. However, it emphasized the realization that a fetus in pregnancy had to be considered differently from adults and that toxic substances could be far more life changing to fetal brains and bodies in development. The question of damaging the brain is very different with children, whose brains are still small and forming, whereas adults have fully-developed brains that may be damaged, but in different ways. Additionally, the great diversity seen among people, and in all living species introduces a potential wide range of variations relating to individual genetic susceptibilities that is known to be reflected into toxicity levels [14]. This is undoubtedly true with neurotoxic illnesses, and is quite likely the basis for the breadth of the so-called “spectrum” of neurological illnesses that are observed. This present analysis of medical data, but with a chemical emphasis, is aimed at highlighting the continuing difficulties encountered in the field of toxicology and examines these questions with the aim of better describing present day neurological risks. In this process, it has been noted that although efforts are being made to better manage the human environment, certain social lifestyle changes now are clearly introducing high risk toxicity levels in some cases of several known neurotoxic elements and could easily be the base cause for the observed neurological damage.

2. The Major Neurotoxicants and Their Toxicity

For neurological epidemics, especially if global in nature, the presence of known neurotoxic sources that are commonplace are necessary. Moreover, our knowledge of the body’s strong blood-brain barrier illustrates how effective it is in separating and processing the toxins and neurotoxin chemicals that are normally ingested [15,16]. For many people, this and the body’s detoxification systems are adequate and are automatically sustained throughout life, from conception to death. However, autopsy data are intriguing in establishing that during life, numerous chemicals do accumulate in the brain. In cases of Alzheimer’s disease deaths, a myriad of elements are seen present in addition to the six neurotoxic elements considered herein [17,18]. Due to this, any individual roles are impossible to isolate [19,20,21,22,23]. Whether some of these observed metals are solely sequestered in the brain in benign neutralizing proteins or are in some type of active balance between the body and brain remains unknown. Additionally, such observations are also reported for fetal brain autopsies reflecting similar metals and confirming the mother/baby close inter-connection. Studies have clearly identified the presence of mercury, for example, that correlates directly to the maternal hair level [24].
The problem of attaching liability to any epidemic in medicine is generally difficult because of the complex inter-connected chemistry in the human body. In any medical study, the consequences of never fully knowing all the controlling parameters necessarily retains uncertainty for any suggested conclusion. This has been illustrated quite recently, notably in the numerous decade-long US studies with the Seychelles’ and Faroe Island’s peoples, concerning their possible neural effects from having significant fish diets, one based more on whale meat, while the other on ocean fish [25,26,27,28,29]. It now appears that an overlooked role played by selenium as a major brain chelator and the varying natural atomic ratio of selenium to mercury in differing fish varieties may be pivotal for any analysis concerning methylmercury’s true toxicity from a seafood diet [30,31,32,33]. If valid, this will now make any nutritional risk/benefit analysis for dietary fish quite involved and in need of re-assessment. However, as mentioned later, it might resolve observed differences in the data reported between these two large cohort studies for fish-mercury.
Concerning neurotoxicants, a recent useful study has extensively examined the current medical databases for chemicals that can be listed as developmental neurotoxicants [34]. The produced list contains about 100 molecules or elements drawn from mainly rodent, but also several human, tests. About 85 of the species listed are organic with six organo-metallic chemicals. This then leaves a surprisingly short list of neurotoxic inorganic elements and their compounds that might be considered, especially as these are encountered to varying extents everywhere in life. They are aluminum (Al), arsenic (As), lead (Pb), manganese (Mn), and mercury (Hg). Selenium (Se) should have been added to their list because it has only a narrow beneficial range of safe dose-levels above which it is also a known neurotoxicant. Thallium, also not listed, is an additional potent neurotoxin but not commonly encountered by the general populace and, if so, is soon apparent [35]. This published list also included cadmium (Cd), not generally labeled in this manner. One publication has reported a correlation for child neurobehavioral development in five-year old children in rural Bangladesh with Cd levels [36]. Whether this is valid awaits more detailed studies when more extensive testing might exclude other possible neurotoxicants that might be biasing the data. Generally, cadmium is regarded solely as a developmental modifier influencing birth statistics, such as baby weight, length, and head circumference [37]. It can be found in brain autopsies, but is not considered a neurotoxin at present [38,39]. As a result, the main elemental inorganic neurotoxicants of concern to the general public center on Al, As, Hg, Pb, Mn, and Se chemistries and merit in depth examination. The first four of these are non-essential to the body and serve no bodily purpose. Animals do appear to have some need for As, but a human requirement still remains debated and uncertain. Mn and Se are known to be essential micronutrients. Mn has a high level for toxicity in humans and cases of death are rare [40] and, as mentioned, Se has one of the narrowest ranges for human accepted needs, displaying dietary deficiency (<40 µg/day) but toxic levels (>400 µg/day) [41]. Reported deaths mainly center on supplements administered to animals, particularly horses, in areas where Se is at low levels in soil and grains [42], and are rare for humans.
The published reference list mentioned above contains many more organic and organo-metallic compounds that also are known neurotoxicants. These are certainly hazardous to humans and cannot be readily disregarded. However, they do differ from the inorganics in generally being man-made and are less commonly encountered in normal human diets, but are present in many dermal or inhalation commercial products. They are also found in agriculture or food processing usage, but to be connected with global epidemics there are further criteria. For example, usage has to be global and newly-implemented in recent decades. Of course new pharmaceutical drugs are appearing annually. However, pre-release testing and initial prescription usage hopefully should indicate problems locally. Additionally, they generally have well-defined specific applications or purposes. As a result, problems generally should be reflected on local or small geographic scales and not be dispersed globally. This was not the case for DDT, of course, which was finally identified as carcinogenic and fortunately not a neurotoxicant for humans. Concern, generally with organic forms, relates more to their being simple toxins or carcinogens, and the public is at risk in this regard. However, it is almost like the drinking of caffeine in coffee: even though this is listed as having neural effects on animals, the risk is accepted, even though it might still have long-term problems for humans. Consequently, if any effect is not sufficiently pronounced some risk is accepted by the public. However, as a result of innumerable studies [43,44], any general global neurological danger to the public from known neurologically-labeled organics is not evidenced at present in the extensive medical literature in connection with these neurological illnesses considered herein. However, birth effects can be noted in other aspects, such as birth weight or head size. Those compounds that have become well-labeled as possibly producing bodily effects are more tightly regulated and are listed and known by the practicing medical profession [45]. For all that, whether some of the unlisted organic chemicals can aggravate or have a minor secondary contribution to the ever human body-burden certainly remains of concern and it would not be at all surprising if some do. One recent review did suggest certain organic pesticides might trigger ADHD in children [46]. Another Japanese study of 322 pregnant women noted 87 biphenyl and dioxin-type organic toxins present in their blood [47]. Although at low levels, such organic chemicals are becoming ubiquitous in humans and whether they induce low-level effects is difficult to measure. This becomes the dilemma. In fact, at what level does an organic toxicant, or mixture of them, become dangerous? This remains largely unchartered waters.
The field of neurotoxicology, when relating to humans, remains an inexact science, especially for these chosen inorganic elements in this study, and is fraught with difficulties. Since human testing remains minimal and difficult for obvious ethical reasons, the bulk of the data have to be obtained from animal studies. In addition, significant other complexities abound. In humans, most toxicants come mainly from diet, with dermic or inhalation routes more a concern in the industrial workplace environment. Additionally, the toxicants can include a wide range of molecular forms that are generally absorbed to varying degrees. Such complexities introduce approximations particularly in scaling from the animal data to humans. This then converts to a toxicity unit of the form toxicant mass/kg human body weight/day. It then has to be scaled further to produce equivalent biomarker levels for medical testing of a preferred body sample, for example, generally for blood, hair, or urine concentrations. As is acknowledged, these conversions are not exact and a compensation factor for the expected errors in these approximations is invoked for an acceptable minimum risk level (MRL) to be recommended. For these elements a lowering generally by two orders of magnitude is preferable, if possible, below the laboratory-implied onset of toxicity, either the NOAEL (no observed adverse effects level) or the slightly higher LOAEL (lowest observed adverse effects level). In other words, to the best of our abilities, when also coupled to any auxiliary human data that may be available, the location of these actual toxicity onsets become reasonably established, but remain with possible errors depending on their source data. They form the basis for the then-recommended lower MRL biomonitoring values that are suggested with a built-in safety buffer of a possibly 10- to 100-fold margin, if this appears reasonable and acceptable. With the neurotoxins, this is the best that can be done at present, but MRL values are not rigid or precise due to the approximations or considerations made and can be modified over time with additional observations. This remains somewhat more unsatisfactory, especially for young children and for pregnancy, where the toxicity level itself may become more uncertain, as well as the scaling models. Questions concerning fetal risk from a growth of being less than a gram in the first eight weeks, to final birth weight are not satisfactorily addressed through a lack of knowledge. Prudence for life should, of course, always have body neurotoxicant levels as low as possible and especially throughout pregnancy. As will be noted, the fetal risk has to be high in all pregnancies and a choice of having low neurotoxic levels may generally not be available.
For any one neurotoxic element, the level of toxicity generally varies from compound to compound, whether inorganic or organometallic, whether water soluble, or with a differing degree of absorption by the body [48]. Some factors also arise concerning valency, particularly for arsenic and mercury. Nevertheless, due to the more involved aspects of monitoring this valence distribution (speciation), particularly in drinking water for arsenic content, it is generally common to simply measure and quote the total amount. However, in fish, arsenic is largely present in a non-toxic organic form (arsenobetaine) that the body cannot metabolize [49]. Mercury is highly neurotoxic in organic forms, such as the methylmercury in fish [50], and thimerosal still used in some vaccines [51,52,53]. However, elemental Hg from tooth amalgams, for example, and most of its divalent inorganic forms normally encountered, are more toxic to the body than the brain. This is due to their difficulty in passing through the blood-brain barrier. Additionally, insoluble cinnabar, HgS, and monovalent calomel, Hg2Cl2 are essentially non-toxic. Nevertheless, by measuring the total As or Hg levels, normally done by several biomarkers, either involving blood, serum, urine, or hair sampling, although not precise and probably in error with regards to overall neurotoxicity, the results do err in the direction of overestimating the suggested body toxicity. A follow up, then, is an option to better analyze the situation.

The Neurotoxic Six Metal Elements and Their Compounds

Although it is the responsibility of health agencies, such as the World Health Organization in Geneva, to establish these MRL (minimum risk level) values, they still remain uncertain and, in some cases, not exactly established or known. Aluminum is one important case for which values that exist still relate to specifically oral ingestion. Examined in great depth in recent decades, this centered mainly on evidence of toxicity from the now-replaced use of aluminum phosphate binders in previous dialysis treatments of kidney failure cases. Studies, then, for such oral ingestion, implied an MRL of 1 mg Al/kg body weight/day [54]. A significantly high level, indicating little risk. However, consumed in such a manner, intestinal absorption is known to be extremely low in the 0.1–0.6% range. Consequently, the recent introduction of aluminum hydroxide as the dominant adjuvant in many US vaccines has now modified the situation and requires renewed studies. Consequences of such inoculations have been analyzed far less, but one very extensive review now accepts that the levels of absorption by the body will be much higher [55]. Additional studies have suggested that this alone is a high medical risk for neurological complications [56,57]. In addition although the documentation concerning the known ingress/egress transport across the blood-brain barrier (BBB) remains hazy for Al, it has been shown to occur [58]. Isotopically-labeled 26Al studies effectively established this with rats suggesting long brain half-lives with indications of its presence also in fetal rat brains [59]. Additionally, intravenous feeding of preterm infants with commercial food products has long been of concern, as well as breast milk, for the possible contaminating Al content [60,61,62]. With any MRL, the unit contains “per kg body weight”. As a result, when applied to children this obviously increases in importance. Of the neurotoxicant inorganic elements, the risks associated with aluminum remain the least certain, its chemistry being predominantly inorganic, and its possible connection with old-age related consequences still remain very heavily debated [63]. Interestingly, aluminum also has recently been blamed as a risk factor in male infertility [64].
Although long known to be a serious neurotoxin, it is only in recent decades that lead’s anthropogenic presence has been more seriously considered. That leaded gasoline, lead in paint, in copper pipe solder, and crystal glass were extensively promoted is now considered unbelievable by many environmentalists. This is especially so with the World Health Organization (WHO) reporting that 143,000 children died globally in 2004 from lead poisoning. No meaningful MRL values are quoted for lead, but extensive toxicological reviews are available [65,66]. The accepted consensus is that any level of lead is unhealthy [67]. However, because a zero-value is not practical with lead’s ever-presence to some degree in the natural environment, it remains that less will always be beneficial and remain an objective purpose. One study of children in 1972 in New Zealand monitored their blood level content. It now reports, 45 years later, that early exposure does have long-term ramifications [68]. Additionally, regrettably, in cities such as Karachi, Pakistan, pregnant women, newborns, and children are still commonly experiencing blood values today in the range 100–500 µg/L when values <50 µg/L are desirable [69]. Due to lead’s continued presence in many locations, only temporary MRL values currently tend to be in use, mainly as a coarse measuring indicator for doctors, and are gradually being lowered as it becomes possible with environmental improvements. Ultimately, as there is a return to low natural levels in the normal environment, a firm and more meaningful MRL target may become possible for lead and imply a safe level for minimal neural damage.
Mercury, another potent neurotoxicant documented through the centuries has also come to the forefront in recent decades. This is mainly through concerns due to its presence as the organometallic thimerosal in vaccines, and also now especially through the added recognized risk associated with the presence of methylmercury in most fish varieties. Environmental pressures have been severe to the extent that mercury is no longer mined globally or used commercially. All its applications in most countries have been banned and remaining anthropogenic sources tend to be solely the unregulated emissions from coal combustion and some cement production, medical uses, its diminishing application in dentistry, and some continued use in artisanal gold mining. Significant efforts by the United Nations and others now are attempting to control such use in mining [70]. Its toxicology is well documented [71,72]. Additionally, monkey blood and brain studies have clearly confirmed organic mercury’s ability to enter the brain. For ethylmercury, from thimerosal, about one-third becomes inorganic and two-thirds remains organic. Therein, the brain half-life for the organic fraction is about 14 days, but 24 days for the total loss of mercury. For methylmercury, it mainly remains as such with a residual brain half-life of about 60 days [73,74]. This had been shown earlier with pregnant hamsters for methylmercury using isotopically-labeled 203Hg added to their diet, finding it in both the brains of mother and fetus [75]. Placing more emphasis on studies considering people on high fish diets, coupled to extensive animal studies, an NOAEL Hg blood level of 60 µg/L was suggested. This led to the U.S. Environmental Protection Agency quoting a recommended MRL blood value of 5.8 µg/L [71], only 10-fold lower, which is now in common usage and will be discussed further below when data are presented.
Extensive toxicological reports have been published for arsenic and suggest an MRL of 5 µg/kg body weight/day [76], also only 10-fold below its LOAEL value. In California under a State Proposition 65, listing controlled chemicals, this limit has been reduced now to 10 µg/person per day, but the new emphasis relates more to the risk of cancer rather than neurological damage. In areas of the world where water can contain concentrations of As > 50 µg/L it is obvious that small children will be at significant risk for both cancer and neural damage. As indicated already, arsenic’s ingestion rate can be complex with biological (organic) forms in seafood generally being non-toxic [49]. Its ingestion is predominantly oral, resulting mainly from drinking water sources. In many parts of the world this is a dominant concern. Average U.S. dietary needs, if any, remain unknown but have been suggested as 12–25 µg/day approximated from animal studies [77]. The LOAEL toxic level is considered to be quite well established in this case. As a result, although arsenic may be of less concern in more developed countries, arsenic in drinking water and edible crops requires close management elsewhere [78,79]. Arsenic is cleared quickly from the blood and generally hair or urine samples are a more meaningful biomarkers of prolonged exposure.
Manganese differs from the above four in being an essential micronutrient to the human diet. At higher dose rates, though, it does become neurotoxic and is known to influx the brain [80,81]. It has been studied extensively in animals and humans, but a firm MRL value remains uncertain. A major toxicological review quotes an interim guidance value of 0.16 mg/kg body weight/day based on a 70 kg adult and an average of about 11 mg/day ingestion [40]. Its use in fungicides, and now as a fuel additive, have raised few concerns thus far. It is present in many foods and can be significant in teas and some herbal drinks. However, potential risks to children and a fetus in pregnancy are labeled as important, but appear to remain a low priority by agencies in spite of possible reported drinking water effects and other concerns [82,83,84,85]. No MRL value is quoted for pregnancy.
Selenium, although a potential neurotoxin, is now being recognized as an extremely important element in the body. The fact that DNA is programed to produce about 26 different seleno-proteins in the body lends support for such a consensus. These now appear to be major chelating antioxidants for cleansing the body and particularly the brain of toxicants. They are capable of removing the above five mentioned neurotoxins, namely Al [86,87], As [88], Pb [89], Mn [90], and Hg [91,92]. Selenium has a significant biological presence in the body. Dietary intake has now been raised from earlier suggestions to a range of 200–300 µg/day for adult good health [93,94], but which is not too far below the toxic level of >400 µg/day [41,95]. Deficiencies certainly need to be satisfied, but abundant levels should not be supplemented.

3. Blood Level Neurotoxins in the General Populace

The advent of improved monitoring capabilities has changed science and medicine, particularly those based on the inductively coupled plasma method in either its optical spectral emission or its more sensitive mass spectrometric modes. It has introduced a flurry of large scale testing programs around the world aimed at obtaining databases and establishing average baseline values of innumerable compounds in blood, hair, and urine or body tissues. This has helped in better-recommended minimum risk levels, particularly for toxins and neurotoxins, and has enabled legislated steps concerning safety levels in the workplace. The first surprise found in all these human media results was the richness of trace chemicals present in the body. One study examined 27 metal elements in blood and serum samples, finding all of these easily, except four, within the level of detection [96]. More ambitious programs have included anthropogenic organic compounds, such as polychlorinated biphenyls (PCBs) and other persistent organic pollutants, and have enlarged this list to display the presence of over a hundred [44,97]. In worldwide blood samples, all the main neurotoxin and toxic inorganic elements are invariably observed. However, analytical sensitivities now are such that the question is not whether something is present but, more importantly, its magnitude. This is where the value of an average or minimum risk level arises and can better guide a medical examination. However, from a scientific point of view, there is one interesting aspect in these large surveys that has not been as strongly emphasized. This concerns not solely the average and its relationship to appropriate MRL values, but more so the spread of the distributions for any of these elements or compounds. It is clearly apparent that people differ significantly, even for groups that have very similar diets and lifestyles. Distributions quite generally can be broad and it is obvious that such variations reflect that some people can shed a toxin more efficiently, while others tend to be retentive.
To examine this aspect of broad distributions further, numerous large blood testing databases from around the world that included neurotoxicant values have been re-examined. Concerning the general populace in various countries, the data for some are compiled in Table 1. Listed are approximate distribution averages, together with maximum values, some estimated from the 95–98% percentile-level of the distribution, and some measured. The databases selected have been chosen from the very many such tabulations only to display these possible variations and trends. Their exactness and reliability are of minor concern here, but they are chosen so as not to be perturbed by any unique environmental aspect, such as a heavy industrialization bias. In all, it was noted that male/female levels for these elements were very similar, except for lead, for which male levels are generally slightly larger. The first thing observed is the very limited data available for blood aluminum levels. This results from the previous lack of concern with dietary or orally-consumed aluminum, which is minimally absorbed by the body. However, now that aluminum hydroxide has become a major adjuvant in most US vaccines, it should certainly be added to future surveys as increased concerns about its use have been raised [55,56,59,98,99]. Those few data that are available do not discuss this potential bias and cannot be realistically analyzed. They do clearly indicate its presence.
As mentioned above, the establishment of satisfactory MRL values are important mainly as a rough guide, but do remain uncertain in several cases. Those for arsenic, manganese, mercury, and selenium have a basis, as described already, from animal and some human data. They are in use at major medical blood-testing centers. The value for mercury listed in Table 1 has been the main recommended US value now for some time, but other countries have modified it, for example, in Germany to 0.8 [115] and two US testing centers use values of either 9.0 or 2.0 µg/L. These together cover an 11-fold range and further illustrates the varying uncertainties and safety risk assessments. As indicated, the case for Al remains very uncertain, with the US Mayo Clinic suggesting the value in Table 1, but another facility stating <30 µg/L [116,117].
The situation remains difficult with Pb, with MRL values being suggested targets rather than being based on the realistically-observed measurements in adults. Germany again suggests a lower value of 35 µg/L for children. However, a major guide at present is to try and maintain the populace below 50–100 µg/L as much as possible. Generally, trends are drifting lower as communities continue the endeavor to minimize this particular hazard. The difficult question is how much larger does an observed value have to be above a suggested MRL level before chelation becomes recommended. At present, this is often when toxic effects are visually present. In cases such as the 2000–2004 crisis of lead in the drinking water of Washington, DC, the consequences are still being documented [118]. Small children suffered from poisoning and there was a high incidence of miscarriages and fetal deaths even for blood levels of 50 µg/L, a value still evident in numerous parts of the world.
Several of these distributions are plotted in Figure 1 to better illustrate the distributions. Generally these are statistically tabulated, but not usually visually drawn in this manner. To some degree this is because of the commonality, and the major interest in average values and their standard deviations. For example, in the present case, a comparison of the lead and mercury profiles shown here do mirror those portrayed previously in a totally differing recent Polish survey [119].
Although basic shapes may stay similar from one survey to another, average values will vary with geographic locations. However, a common aspect is the long outlier tails that can extend well beyond the 95 percentile level and, in most, cases many-fold above the average value. The profile for selenium appears to differ considerably from the others in seemingly being tightly controlled between its extremes in numerous surveys. Although its average can vary, the shape seems to be quite common. Nevertheless, studying all these surveys, values can stretch quite significantly above the average, and sometimes do extend to ten-fold, or more, above the MRL value. In other words, the toxicological efforts to safeguard society appear reasonably valid for the general populace. However, in the outlier cases, these approach and can venture into the toxicity curve region. For example, in one US survey with 1800 blood-lead samples, 4.8% of the distribution was ≥50 µg/L, including 12 women of reproductive age; eight samples were ≥100 µg/L, and two were ≥250 µg/L [113]. Extreme examples are commonly seen to exist.
In addition to considering the neurotoxins individually, this, of course, overlooks an obvious question: How does the human body simultaneously respond to multiple toxins? For the majority of people, observations do confirm that the body mechanisms appear to be sufficient to control most neurotoxins. However, as mentioned below, synergistic factors between various trace metals have now been reported. Additionally, the fact that society is presently documenting mercury poisoning cases in adults illustrates that the above safeguards are failing at times [120]. Additionally, there is no measure available to indicate only slight neurological effects that might be accumulating over time.

4. Blood Level Neurotoxins in Pregnant Women

Due to the known major risks concerning pregnancies, even more extensive databases have been generated measuring toxicants in a mother’s blood during the stages of pregnancy and in the baby’s umbilical cord at birth. A similar sampling of data are listed in Table 2. Again, this shows an average and a suggested maximum value for each statistical distribution. Some of these databases provide information on the full distribution and are further illustrated in Figure 2.
As already noted in Figure 1, the maximum value recorded or estimated is also shown in parentheses. Comparing Figure 1 and Figure 2 is difficult in that quantitative magnitudes can vary significantly from country to country depending on their location and environment. Nevertheless, the distributions can have similar shapes. All display the steep rise at lower values where the majority of samples are located, and then a more gradual fall-off representing the fraction lying above the average and with wider variability. In Figure 2, two profiles are displayed for Hg to indicate how differences may occur from one survey to another. However, even in these cases, although one is narrower, it has the longer extended tail. Other than for Se, there really are no noteworthy differences between the general or pregnant women distributions.
Even in pregnancy, average values do not exhibit drastic reductions, even though one might expect greater diligence now as expectant mothers are becoming better warned of dietary risk factors. Whether the noticeable change in distribution for selenium with pregnancy seen in Figure 2 is meaningful requires confirmation, but the distribution seems to broaden and extend to much higher values. Whether this suggests some importance for selenium’s chelating, anti-oxidant role remains too speculative. The main aspect of the current analysis is to illustrate the extension of outlier values that can stretch many-fold above the average and is common for all these toxicants. Of course the blood concentrations of expectant mothers will be biased already at conception. Whether their levels can be reduced significantly by dietary changes requires testing. As a result, the major conclusion from Figure 1 and Figure 2 is simply that everyone, pregnant or not, can have noticeable levels of these blood neurotoxicants. Moreover, at present, there appear to be no major differences seen between the general populace and pregnancy. A recent extensive review summarizes the blood levels during pregnancy for Pb, Hg, and Cd in various surveys taken after 2000. The review stresses the need for much better MRL values, especially for pregnancy. However, it also reiterates that, realistically, there are no safe blood-level values for any of the heavy metals during pregnancy [137].
Placental protection of the fetal blood has been very extensively studied. A recent review has been published of the birth-cord blood to maternal-blood concentration ratio of innumerable elements and compounds from more than 100 studies [139]. For the six principal neurotoxicants discussed here, the placenta is seen to be very pervious. For lead and selenium this ratio is close to unity, arsenic is slightly below unity, but rather surprising, mercury and manganese are two- to three-fold larger in the fetal blood. That for aluminum remains unclear, but the cord blood was high in one study [122] and the ratio might have been about a half or slightly protective in others [140,141]. Nevertheless, isotopically-labeled studies on pregnant rats have clearly identified Al transfer into the brain of their fetus [59]. Clearly, the placenta is incapable of protecting a human fetus with regards to neurotoxicants or most other heavy metals.
As noted above, toxicology utilizes in its unit, “quantity per body-weight”. The fetus starts from a minimal body-weight and is only about 1 g at eight weeks. As a result, and with this minimal placental protection, the important question is “what is the safe MRL for a fetus and how does it even survive?” Few medical papers appear to have addressed this aspect. One that did analyzed the situation primarily for mercury, concluding that the fetus was always at very high risk [142]. This would appear to remain valid and the only conclusion to be logically drawn is that the fetus must have a very efficient blood/brain barrier from initiation and/or additional protective mechanisms as yet unknown.

5. Why Now?

The fact that society is now displaying changes in neurological health appears undeniable. Care centers are appearing everywhere and publications concerning neurological health are more extensive. The general consensus is that this is not a primary result of genetic changes or improved diagnosis, but more probably results from the environmental complexity of our modern age. Present-day monitoring capability has illustrated in the results listed herein that human bodies are now constantly being contaminated by dietary and commercial product ingredients. Although society is continually introducing stricter controls, and significant steps forward are being made in some areas, at the same time life-styles are constantly changing. However, if neurological epidemics are a consequence, this has to be reflected by some societal change that has occurred in recent decades.
To affect pregnancy on a global scale this has to involve a change of ingestion of neurotoxicants either from the air, diet, or medically. In normal life, the three-dimensional dilution of pollutants in air can generally eliminate any noticeable levels of neurotoxicant intake directly from this. As a result, the logic suggests a necessary increase must have occurred in the diet or some medical protocol. This implies that some people are going beyond their body’s limits that are defined by their individual genetic nature. An additional factor, not yet addressed, is that our measured toxicology data mainly relates to the safety aspects of substances when considered singularly. More and more, in life and science, the addition of multiple factors coupled to aspects of synergism are becoming evident. This has been studied medically in the body mainly in how its complex balances may be modified by added changes. Some aspects of synergistic effects for mixtures of toxins have been noted in human body organs [143], but very few studies are yet available to examine such effects with neurotoxicants. One such important examination looked at long-term exposure of mice to low doses of Pb, Hg, As, and Cd individually and in their mixtures [144]. This extended and confirmed earlier work on rats with Pb, As, and Mn [145]. These very clearly indicated that the neurotoxin elements could be affected by other toxins or even other essential metal elements in a synergistic manner, certainly enhancing their presence in the brain of animals. This has now generated interest in the possible mechanisms of such interactions [146]. In other words, from the point of view of toxicology of the brain, there remains a depth of uncertainty. It is partly a complex chemical kinetic problem that depends on brain ingress and egress rates, lifetimes in the brain, and how quickly neutralization or sequestration occurs for anything that may be held there. Additionally, on rates of damage and whether this can be repaired [147], or replaced by surplus circuitry, very little such data yet exist, except some for particularly organic-mercury in animals. In that case, research has now introduced the aspect that elevated levels of Se do appear to protect the brain against Hg in mice and rats, and that neutralization mechanisms in the brain may, in fact, be quite rapid [92,148]. Moreover, one study on rats even reported a reversal of Hg toxicity when their diet was switched to one that was Se-rich [149]. Furthermore, some Japanese residents who consume significant levels of whale meat and display dangerously high levels of methylmercury in their hair and blood, show minimal neurological damage. On analysis, it is apparent that their blood Hg/Se atomic ratios are always less than unity and it is concluded that the Se may alleviate their risk [30]. Many other studies are now stressing this possible importance of the Se/Hg atomic ratio in fish [150,151]. Additionally, numerous new studies now are underway concerning the benefits of Se [152,153], during pregnancy [154], for the elderly [155,156,157], and a possible role for this in Alzheimer’s disease treatment [158,159,160,161,162,163].
It is evident we need knowledge of these six neurotoxicants in the body, and lifestyle control is necessary to maintain them at a safe level, not only individually, but probably their summation. Since the epidemic of neurological illnesses has mainly occurred in the last 30 years, the causal effect has to be compatible with such a time-frame. One such exercise was recently completed, relevant particularly to the US [164]. It indicated that the three- to four-fold increase in vaccination schedules, coupled to the introduction of social “Japanese-style” sushi additions to the diet in this same time period could be excessive. When considered together they closely correlated with the growth of autism. The present analysis lends supports for such a conclusion. Additions of other minor sources with possible synergistic contributions can readily overburden the body’s ability to remove such toxicants in some fraction of the human population. In pregnancy, the fetus is even more vulnerable due to its small size. Additional concerns are now suggested by the increasing rates of miscarriages, not only in industrialized areas, but also in sub-Saharan countries, all being linked to the presence of heavy metals [118,165,166,167,168]. Another aspect is the possible transport in semen [169], and the general role of trace metals in the fertility of both males and females [170,171]. Additionally, the risk of small accumulation rates in the brain over a lifetime can no longer be ignored.

6. Conclusions

Societies often are content with their status quo until a problem arises; then it has generally been normal to look for the cause, usually singular, and correct it. With the current epidemic of neurological illnesses, both in the young and the old, this has been increasing rapidly over the last 20–25 years with no resolution. A tremendous wealth of medical research has questioned the potential roles of known neurotoxicants, organic or inorganic, indicating that not one of these clearly stands out. Vaccines have been extensively questioned [51,52,53,56,172], but testing has always appeared to confirm their safety. However, it is true that some disturbing evidence is apparent otherwise. One report noted the enhanced rate of miscarriages in the US during the 2009/2010 influenza vaccine period [173]. For the first and last time, pregnant women were given two different influenza vaccines instead of the normal one during any trimester. They both contained thimerosal. The analysis showed that miscarriages that year increased by more than an order of magnitude compared to earlier or later years. It remained unexplained. The attempted emphasis on a single cause has now changed, and numerous studies other than this one are beginning to suggest the possibility that combined factors do enhance the risk involved, with possibly additional synergistic effects [146,164,174]. The present study, with a more chemical, scientific approach, extends this further, and now appears to clearly exhibit that this has the potential, in some cases, to overload both humans and fetuses with neurotoxicants. It is very plausible and satisfies the necessary criteria. Consequently, if the risk of neurological damage is to be reduced, changes will have to be made to various lifestyles. In fact, even three years ago, the United States EPA indicated grave concern over the increasing chronic methylmercury exposure from fish consumption [175]. Moreover, several groups have already realized the significant value in taking such a step by analyzing cost and intellectual benefits that would result from reducing neurological damage [176,177]. Nevertheless, this will be difficult. For example, obstetricians today are faced with assessing the risk concerning a fish diet during pregnancy [178,179]. This has become an even more difficult risk analysis calculation especially if the moderating aspects of selenium are correct. Consequently, although the average mercury content of most fish varieties have now been listed, they may need repeating, to list the corresponding Se content [180]. Additionally, governmental changes and directives are clearly needed concerning vaccines and any neurotoxic content. Canada is one country that already has taken action, particularly with regard to safer vaccines for pregnancy [176].
To be prudent, one important step would be to initiate testing to establish the baseline values of these neurotoxicant metals in all women of child-bearing ages. In some cases waiting until pregnancy may be too late and this might also reduce the high rates of miscarriages that now are reported. A one-time testing when young could be sufficient for most women and clearly identify those with levels controlled by diet or a genetic susceptibility. This would significantly reduce anxiety concerns in all women and be of value to health. In cases where higher level susceptibilities were found, adequate modification to diet could be implemented [181]. Men, would also probably like to know their category of genetics, whether they were below or above average with regards to retention, and this could possibly aid in resolving fertility questions. It would remove a presently unknown aspect of our body that exists. If necessary, sources of drinking water might be analyzed for content and treated. In the US, lead might be of concern in older homes due to old paint, the solder used on copper pipes, or even lead piping in some communities. Additionally, the medical profession has to reassess its current general vaccination program. Although there is no denying this has been a tremendous success, it has now grown three- to four-fold in size in the last 30 years and has become excessive. It is twice as large as any other country [182]. By six years old, a child in the US can have 35 inoculations that increase to a total, ten years later, of about 45. It can no longer be denied that this is contributing to body-burden, especially if administered in multiple doses at the same time. Such a practice has to be considered dangerous, irresponsible, and certainly should be ended. Furthermore, development and use of alternate adjuvants for neurotoxicant-free vaccines is critically needed.
Additionally, a very difficult aspect that is still increasing is the extent of certain fish in diets. Its nutritional value is beyond question, but the risk, particularly for young women, is severe, requiring guidance. Moreover, this risk is present for all children, and even for adults. Even with the brain’s protective mechanisms, and possibly adequate Se content, the extent of minimal damage from even small doses of neurotoxicants, such as methylmercury, remains unknown. Many toxicologists are now suggesting the true safe-level for any neurotoxin is as close to zero as possible. The assumption that the body is resilient and can accept a certain level of abuse is, at best, unwise. Potential biomarkers are now available to better minimize risk before the onset of damage occurs and should be considered very seriously, especially as life-span increases [183]. Low-level goals are certainly prudent. The toxins and neurotoxicants, with several exceptions, have always been in the human diet from natural sources, however, we have no measure in history to indicate what spectrum of damage they may have created. It may still be hoped that the body can normally control low levels without long-term ramifications.

Acknowledgments

I am most grateful for the continued support of the facilities of the University of California Library services. Additionally, without private financial support this analysis would not have been possible.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Wright, K. Our preferred poison. Discover 2005, 26, 58–65. [Google Scholar]
  2. O’Malley, G.F. The blood of my veins-mercury, Minamata and the soul of Japan. Clin. Toxicol. 2017, 55, 934–938. [Google Scholar] [CrossRef] [PubMed]
  3. Sealey, L.A.; Hughes, B.W.; Sriskanda, A.N.; Guest, J.R.; Gibson, A.D.; Johnson-Williams, L.; Pace, D.G.; Bagasra, O. Environmental factors in the development of autism spectrum disorders. Environ. Int. 2016, 88, 288–298. [Google Scholar] [CrossRef] [PubMed]
  4. Fujiwara, T.; Morisaki, N.; Honda, Y.; Sampei, M.; Tani, Y. Chemicals, nutrition, and autism spectrum disorder: A mini-review. Front. Neurosci. 2016, 10, 174. [Google Scholar] [CrossRef] [PubMed]
  5. Christensen, D.L.; Baio, J.; van Naarden Braun, K.; Bilder, D.; Charles, J.; Constantino, J.N.; Daniels, J.; Durkin, M.S.; Fitzgerald, R.T.; Kurzius-Spencer, M.; et al. Prevalence and characteristics of autism spectrum disorder among children aged 8 years: Autism and developmental disabilities monitoring network, 11 sites, United States, 2012. Surveill. Summ. 2016, 65, 1–23. [Google Scholar] [CrossRef] [PubMed]
  6. Kamimura-Nishimura, K.; Froehlich, T.; Chirdkiatgumchai, V.; Adams, R.; Fredstrom, B.; Manning, P. Autism spectrum disorders and their treatment with psychotropic medications in a nationally representative outpatient sample: 1994–2009. Ann. Epidemiol. 2017, 27, 448–453. [Google Scholar] [CrossRef] [PubMed]
  7. Jerome, L.; Segal, A.; Habinski, L. What we know about ADHD and driving risk: A literature review, meta-analysis and critique. J. Can. Acad. Child Adolesc. Psychiatry 2006, 15, 105–125. [Google Scholar] [PubMed]
  8. Hickman, R.A.; Faustin, A.; Wisniewski, T. Alzheimer disease and its growing epidemic: Risk factors, biomarkers, and the urgent need for therapeutics. Neurol. Clin. 2016, 34, 941–953. [Google Scholar] [CrossRef] [PubMed]
  9. Brewer, G.J. Copper-2 hypothesis for causation of the current Alzheimer’s disease epidemic together with dietary changes that enhance the epidemic. Chem. Res. Toxicol. 2017, 30, 763–768. [Google Scholar] [CrossRef] [PubMed]
  10. Vaz, F.N.C.; Fermino, B.L.; Haskel, M.V.L.; Wouk, J.; de Freitas, G.B.L.; Fabbri, R.; Montagna, E.; Rocha, J.B.T.; Bonini, J.S. The relationship between copper, iron, and selenium levels and Alzheimer’s disease. Biol. Trace Elem. Res. 2017. [Google Scholar] [CrossRef] [PubMed]
  11. Chakraborty, P. Mercury exposure and Alzheimer’s disease in India: An imminent threat? Sci. Total Environ. 2017, 589, 232–235. [Google Scholar] [CrossRef] [PubMed]
  12. Canevelli, M.; Blasimme, A.; Cesari, M. Societal and global implications of the “dementia epidemic”: The example of the London Heathrow airport. Eur. J. Epidemiol. 2017, 32, 347–348. [Google Scholar] [CrossRef] [PubMed]
  13. Stromland, K.; Nordin, V.; Miller, M.; Akerstrom, B.; Gillberg, C. Autism in Thalidomide embryopathy: A population study. Dev. Med. Child Neurol. 1994, 36, 351–356. [Google Scholar] [CrossRef] [PubMed]
  14. Jager, T. All individuals are not created equal: Accounting for individual variation in fitting life-history responses to toxicants. Environ. Sci. Technol. 2013, 47, 1664–1669. [Google Scholar] [CrossRef] [PubMed]
  15. Everts, S. Brain barrier. Chem. Eng. News 2007, 85, 33–36. [Google Scholar] [CrossRef]
  16. Bauer, H.-C.; Krizbai, I.A.; Bauer, H.; Traweger, A. “You shall not pass”: Tight junctions of the blood brain barrier. Front. Neurosci. 2014, 8, 392. [Google Scholar] [CrossRef] [PubMed]
  17. Szabo, S.T.; Harry, G.J.; Hayden, K.M.; Szabo, D.T.; Birnbaum, L. Comparison of metal levels between postmortem brain and ventricular fluid in Alzheimer’s disease and non-demented elderly controls. Toxicol. Sci. 2016, 150, 292–300. [Google Scholar] [CrossRef] [PubMed]
  18. Prakash, A.; Dhaliwal, G.K.; Kumar, P.; Majeed, A.B. Brain biometals and Alzheimer’s diseases: Boon or bane? Int. J. Neurosci. 2017, 127, 99–108. [Google Scholar] [CrossRef] [PubMed]
  19. Kasa, P.; Szerdahelyi, P.; Wisniewski, H.M. Lack of topographical relationship between sites of aluminum deposition and senile plaques in the Alzheimer’s disease brain. Acta Neuropathol. 1995, 90, 526–531. [Google Scholar] [CrossRef] [PubMed]
  20. Walton, J.R. Aluminum in hippocampal neurons from humans with Alzheimer’s disease. Neurotoxicology 2006, 27, 385–394. [Google Scholar] [CrossRef] [PubMed]
  21. Bhattacharjee, S.; Zhao, Y.; Hill, J.M.; Culicchia, F.; Kruck, T.P.; Percy, M.E.; Pogue, A.I.; Walton, J.R.; Lukiw, W.J. Selective accumulation of aluminum in cerebral arteries in Alzheimer’s disease. J. Inorg. Biochem. 2013, 126, 35–37. [Google Scholar] [CrossRef] [PubMed]
  22. Exley, C.; Vickers, T. Elevated brain aluminum and early onset Alzheimer’s disease in an individual occupationally exposed to aluminum: A case report. J. Med. Case Rep. 2014, 8. [Google Scholar] [CrossRef] [PubMed]
  23. Wise, J. Higher levels of mercury in brain are not linked to increased risk of Alzheimer’s, study finds. Br. Med. J. 2016, 352, i611. [Google Scholar] [CrossRef] [PubMed]
  24. Cernichiari, E.; Brewer, R.; Myers, G.J.; Marsh, D.O.; Lapham, L.W.; Cox, C.; Shamlaye, C.F.; Berlin, M.; Davidson, P.W.; Clarkson, T.W. Monitoring methylmercury during pregnancy: Maternal hair predicts fetal brain exposure. Neurotoxicology 1995, 16, 705–710. [Google Scholar] [PubMed]
  25. Davidson, P.W.; Cory-Slechta, D.A.; Thurston, S.W.; Huang, L.S.; Shamlaye, C.F.; Gunzler, D.; Watson, G.E.; van Wijngaarden, E.; Zareba, G.; Klein, J.D.; et al. Fish consumption and prenatal methylmercury exposure: Cognitive and behavioral outcomes in the main cohort at 17 years from the Seychelles child development study. Neurotoxicology 2011, 32, 711–717. [Google Scholar] [CrossRef] [PubMed]
  26. Van Wijngaarden, E.; Thurston, S.W.; Myers, G.J.; Harrington, D.; Cory-Slechta, D.A.; Strain, J.J.; Watson, G.E.; Zareba, G.; Love, T.; Henderson, J.; et al. Methylmercury exposure and neurodevelopmental outcomes in the Seychelles child development study main cohort at age 22 and 24 years. Neurotoxicol. Teratol. 2017, 59, 35–42. [Google Scholar] [CrossRef] [PubMed]
  27. Yorifuji, T.; Murata, K.; Bjerve, K.S.; Choi, A.L.; Weihe, P.; Grandjean, P. Visual evoked potentials in children prenatally exposed to methylmercury. Neurotoxicology 2013, 37, 15–18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Jacobson, J.L.; Muckle, G.; Ayotte, P.; Dewailly, E.; Jacobson, S.W. Relation of prenatal methylmercury exposure from environmental sources to childhood IQ. Environ. Health Perspect. 2015, 123, 827–833. [Google Scholar] [CrossRef] [PubMed]
  29. Debes, F.; Weihe, P.; Grandjean, P. Cognitive deficits at age 22 years associated with prenatal exposure to methylmercury. Cortex 2016, 74, 358–369. [Google Scholar] [CrossRef] [PubMed]
  30. Nakamura, M.; Hachiya, N.; Murata, K.-Y.; Nakanishi, I.; Kondo, T.; Yasutake, A.; Miyamoto, K.-I.; Ser, P.H.; Omi, S.; Furusawa, H.; et al. Methylmercury exposure and neurological outcomes in Taiji residents accustomed to consuming whale meat. Environ. Int. 2014, 68, 25–32. [Google Scholar] [CrossRef] [PubMed]
  31. Polak-Juszczak, L. Selenium and mercury molar ratios in commercial fish from the Baltic Sea: Additional risk assessment criterion for mercury exposure. Food Control 2015, 50, 881–888. [Google Scholar] [CrossRef]
  32. Squadrone, S.; Benedetto, A.; Brizio, P.; Prearo, M.; Abete, M.C. Mercury and selenium in European catfish (Silurus glanis) from Northern Italian rivers: Can molar ratio be a predictive factor for mercury toxicity in a top predator? Chemosphere 2015, 119, 24–30. [Google Scholar] [CrossRef] [PubMed]
  33. Ser, P.H.; Omi, S.; Shimizu-Furusawa, H.; Yasutake, A.; Sakamoto, M.; Hachiya, N.; Konishi, S.; Nakamura, M.; Watanabe, C. Differences in the responses of three plasma selenium containing proteins in relation to methylmercury exposure through consumption of fish/whales. Toxicol. Lett. 2017, 267, 53–58. [Google Scholar] [CrossRef] [PubMed]
  34. Mundy, W.R.; Padilla, S.; Breier, J.M.; Crofton, K.M.; Gilbert, M.E.; Herr, D.W.; Jensen, K.F.; Radio, N.M.; Raffaele, K.C.; Schumacher, K.; et al. Expanding the test set: Chemicals with potential to disrupt mammalian brain development. Neurotoxicol. Teratol. 2015, 52, 25–35. [Google Scholar] [CrossRef] [PubMed]
  35. Tanaka, J.; Yonezawa, T.; Ueyama, M. Acute thallotoxicosis: Neuropathological and spectrophotometric studies on an autopsy case. J. Toxicol. Sci. 1978, 3, 325–334. [Google Scholar] [CrossRef] [PubMed]
  36. Kippler, M.; Tofail, F.; Hamadani, J.D.; Gardner, R.M.; Grantham-McGregor, S.M.; Bottai, M.; Vahter, M. Early-life cadmium exposure and child development in 5-year old girls and boys: A cohort study in rural Bangladesh. Environ. Health Perspect. 2012, 120, 1462–1468. [Google Scholar] [CrossRef] [PubMed]
  37. Johnston, J.E.; Valentiner, E.; Maxson, P.; Miranda, M.L.; Fry, R.C. Maternal cadmium levels during pregnancy associated with lower birth weight in infants in a North Carolina cohort. PLoS ONE 2014, 9, e109661. [Google Scholar] [CrossRef] [PubMed]
  38. Faroon, O.; Ashizawa, A.; Wright, S.; Tucker, P.; Jenkins, K.; Ingerman, L.; Rudisill, C. Toxicological Profile for Cadmium; Agency for Toxic Substances and Disease Registry: Atlanta, GA, USA, 2012; p. 487. Available online: http://www.atsdr.cdc.gov/ (accessed on 29 November 2017).
  39. Sigel, A.; Sigel, H.; Sigel, R.K.O. (Eds.) Cadmium from Toxicity to Essentiality; Metal Ions in Life Sciences; Springer: Dordrecht, The Netherlands, 2013; Volume 11, p. 588. [Google Scholar]
  40. Williams, M.; Todd, G.D.; Roney, N.; Crawford, J.; Coles, C.; McClure, P.R.; Garey, J.D.; Zaccaria, K.; Citra, M. Toxicological Profile for Manganese; Agency for Toxic Substances and Disease Registry: Atlanta, GA, USA, 2012; p. 556. Available online: http://www.atsdr.cdc.gov/ (accessed on 29 November 2017).
  41. Fordyce, F. Selenium geochemistry and health. AMBIO 2007, 36, 94–97. [Google Scholar] [CrossRef]
  42. Desta, B.; Maldonado, G.; Reid, H.; Puschner, B.; Maxwell, J.; Agasan, A.; Humphreys, L.; Holt, T. Acute selenium toxicosis in polo ponies. J. Vet. Diagn. Investig. 2011, 23, 623–628. [Google Scholar] [CrossRef] [PubMed]
  43. Nishijo, M.; Pham, T.T.; Nguyen, A.T.; Tran, N.N.; Nakagawa, H.; Hoang, L.V.; Tran, A.H.; Morikawa, Y.; Ho, M.D.; Kido, T.; et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin in breast milk increases autistic traits of 3-year-old children in Vietnam. Mol. Psychiatry 2014, 19, 1220–1226. [Google Scholar] [CrossRef] [PubMed]
  44. Long, M.H.; Knudsen, A.-K.S.; Pedersen, H.S.; Bonefeld-Jorgensen, E.C. Food intake and serum persistent organic pollutants in the Greenlandic pregnant women: The ACCEPT sub-study. Sci. Total Environ. 2015, 529, 198–212. [Google Scholar] [CrossRef] [PubMed]
  45. Ostrea, E.M., Jr.; Mantaring, J.B., III; Silvestre, M.A. Drugs that affect the fetus and newborn infant via the placenta or breast milk. Pediatr. Clin. N. Am. 2004, 51, 539–579. [Google Scholar] [CrossRef] [PubMed]
  46. Polanska, K.; Jurewicz, J.; Hanke, W. Review of current evidence on the impact of pesticides, polychlorinated biphenyls and selected metals on attention deficit/hyperactivity disorder in children. Int. J. Occup. Med. Environ. Health 2013, 26, 16–38. [Google Scholar] [CrossRef] [PubMed]
  47. Miyashita, C.; Sasaki, S.; Saijo, Y.; Okada, E.; Kobayashi, S.; Baba, T.; Kajiwara, J.; Todaka, T.; Iwasaki, Y.; Nakazawa, H.; et al. Demographic, behavioral, dietary, and socioeconomic characteristics related to persistent organic pollutants and mercury levels in pregnant women in Japan. Chemosphere 2015, 133, 13–21. [Google Scholar] [CrossRef] [PubMed]
  48. Yokel, R.A.; Lasley, S.M.; Dorman, D.C. The speciation of metals in mammals influences their toxicokinetics and toxicodynamics and therefore human health risk assessment. Toxicol. Environ. Health B Crit. Rev. 2006, 9, 63–85. [Google Scholar] [CrossRef] [PubMed]
  49. Dopp, E.; Kligerman, A.D.; Diaz-Bone, R.A. Organoarsenicals: Uptake, metabolism and toxicity. In Metal Ions in Life Sciences: Volume 7. Organometallics in Environment and Toxicology; Sigel, A., Sigel, H., Sigel, R.K.O., Eds.; Royal Society of Chemistry: London, UK, 2010; Chapter 7; pp. 231–265. [Google Scholar]
  50. Ceccatelli, S.; Dare, E.; Moors, M. Methylmercury-induced neurotoxicity and apoptosis. Chem. Biol. Interact. 2010, 188, 301–308. [Google Scholar] [CrossRef] [PubMed]
  51. Hooker, B.; Kern, J.; Geier, D.; Haley, B.; Sykes, L.; King, P.; Geier, M. Methodological issues and evidence of malfeasance in research purporting to show Thimerosal in vaccines is safe. BioMed Res. Int. 2014, 8, 247218. [Google Scholar] [CrossRef] [PubMed]
  52. Geier, D.A.; Kern, J.K.; Geier, M.R. Increased risk for an atypical autism diagnosis following Thimerosal-containing vaccine exposure in the United States: A prospective longitudinal case-control study in the vaccine safety datalink. J. Trace Elem. Med. Biol. 2017, 42, 18–24. [Google Scholar] [CrossRef] [PubMed]
  53. Dorea, J.G. Low-dose Thimerosal in pediatric vaccines: Adverse effects in perspective. Environ. Res. 2017, 152, 280–293. [Google Scholar] [CrossRef] [PubMed]
  54. Keith, S.; Jones, D.; Rosemond, Z.; Ingerman, L.; Chappell, L. Toxicological Profile for Aluminum; Agency for Toxic Substances and Disease Registry: Atlanta, GA, USA, 2008; p. 357. Available online: http://www.atsdr.cdc.gov/ (accessed on 29 November 2017).
  55. Krewski, D.; Yokel, R.A.; Nieboer, E.; Borchelt, D.; Cohen, J.; Harry, J.; Kacew, S.; Lindsay, J.; Mahfouz, A.M.; Rondeau, V. Human health risk assessment for aluminum, aluminum oxide and aluminum hydroxide. J. Toxicol. Environ. Health B 2007, 10, 1–269. [Google Scholar] [CrossRef] [PubMed]
  56. Tomljenovic, L.; Shaw, C.A. Do aluminum vaccine adjuvants contribute to the rising prevalence of autism? J. Inorg. Biochem. 2011, 105, 1489–1499. [Google Scholar] [CrossRef] [PubMed]
  57. Tomljenovic, L. Aluminum and Alzheimer’s disease: After a century of controversy, is there a plausible link? J. Alzheimer’s Dis. 2011, 23, 567–598. [Google Scholar] [CrossRef]
  58. Yokel, R.A. Brain uptake, retention, and efflux of aluminum and manganese. Environ. Health Perspect. 2002, 110 (Suppl. 5), 699–704. [Google Scholar] [CrossRef] [PubMed]
  59. Yumoto, S.; Nagai, H.; Matsuzaki, H.; Matsumura, H.; Tada, W.; Nagatsuma, E.; Kobayashi, K. Aluminum incorporation into the brain of rat fetuses and sucklings. Brain Res. Bull. 2001, 55, 229–234. [Google Scholar] [CrossRef]
  60. Bishop, N.J.; Morley, R.; Day, J.P.; Lucas, A. Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions. N. Engl. J. Med. 1997, 336, 1557–1561. [Google Scholar] [CrossRef] [PubMed]
  61. Burrell, S.A.; Exley, C. There is (still) too much aluminum in infant formulas. BMC Pediatr. 2010, 10, 63. [Google Scholar] [CrossRef] [PubMed]
  62. Dorea, J.G.; Marques, R.C. Infants’ exposure to aluminum from vaccines and breast milk during the first 6 months. J. Expo. Sci. Environ. Epidemiol. 2010, 20, 598–601. [Google Scholar] [CrossRef] [PubMed]
  63. Maya, S.; Prakash, T.; Madhu, K.D.; Goli, D. Multifaceted effects of aluminum in neurodegenerative diseases: A review. Biomed. Pharmacother. 2016, 83, 746–754. [Google Scholar] [CrossRef] [PubMed]
  64. Klein, J.P.; Mold, M.; Mery, L.; Cottier, M.; Exley, C. Aluminum content of human semen: Implications for semen quality. Reprod. Toxicol. 2014, 50, 43–48. [Google Scholar] [CrossRef] [PubMed]
  65. Abadin, H.; Ashizawa, A.; Stevens, Y.W.; Llados, F.; Diamond, G.; Sage, G.; Citra, M.; Quinones, A.; Bosch, S.J.; Swarts, S.G. Toxicological Profile for Lead; Agency for Toxic Substances and Disease Registry: Atlanta, GA, USA, 2007; p. 582. Available online: http://www.atsdr.cdc.gov/ (accessed on 29 November 2017).
  66. Final Review of Scientific Information on Lead; United Nations Environment Program: Nairobi, Kenya, 2010; p. 332. Available online: http://www.unep.org (accessed on 29 November 2017).
  67. Vorvolakos, T.; Arseniou, S.; Samakouri, M. There is no safe threshold for lead exposure: A literature review. Psychiatriki 2016, 27, 204–214. [Google Scholar] [CrossRef] [PubMed]
  68. Reuben, A.; Caspi, A.; Belsky, D.W.; Broadbent, J.; Harrington, H.; Sugden, K.; Houts, R.M.; Ramrakha, S.; Poulton, R.; Moffitt, T.E. Association of childhood blood lead levels with cognitive function and socioeconomic mobility between childhood and adulthood. J. Am. Med. Assoc. 2017, 317, 1244–1251. [Google Scholar] [CrossRef] [PubMed]
  69. Fatmi, Z.; Sahito, A.; Ikegami, A.; Mizuno, A.; Cui, X.; Mise, N.; Takagi, M.; Kobayashi, Y.; Kayama, F. Lead exposure assessment among pregnant women. Newborns and children: Case study from Karachi, Pakistan. Int. J. Environ. Res. Public Health 2017, 14, 413. [Google Scholar] [CrossRef] [PubMed]
  70. McDaniels, J.; Chouinard, R.; Veiga, M.M. Appraising the global mercury project: An adaptive management approach to combating mercury pollution in small-scale gold mining. Int. J. Environ. Pollut. 2010, 41 (Suppl. 3–4), 242–258. [Google Scholar] [CrossRef]
  71. Risher, J. Toxicological Profile for Mercury; Agency for Toxic Substances and Disease Registry: Atlanta, GA, USA, 1999; p. 676. Available online: http://www.atsdr.cdc.gov/ (accessed on 29 November 2017).
  72. Syversen, T.; Kaur, P. The toxicology of mercury and its compounds. J. Trace Elem. Med. Biol. 2012, 26, 215–226. [Google Scholar] [CrossRef] [PubMed]
  73. Burbacher, T.M.; Shen, D.D.; Liberato, N.; Grant, K.S.; Cernichiari, E.; Clarkson, T. Comparison of blood and brain levels in infant monkeys exposed to methylmercury or vaccines containing thimerosal. Environ. Health Perspect. 2005, 113, 1015–1021. [Google Scholar] [CrossRef] [PubMed]
  74. Dorea, J.G.; Farina, M.; Rocha, J.B.T. Toxicity of ethylmercury (and Thimerosal): A comparison with methylmercury. J. Appl. Toxicol. 2013, 33, 700–711. [Google Scholar] [CrossRef] [PubMed]
  75. Dock, L.; Rissanen, R.-L.; Vahter, M. Demethylation and placental transfer of methyl mercury in the pregnant hamster. Toxicology 1994, 94, 131–142. [Google Scholar] [CrossRef]
  76. Atsdr, U. Toxicological Profile for Arsenic; Agency for Toxic Substances and Disease Registry: Atlanta, GA, USA, 2007; p. 559. Available online: http://www.atsdr.cdc.gov/ (accessed on 29 November 2017).
  77. World Health Organization. Trace Elements in Human Nutrition and Health; World Health Organization: Geneva, Switzerland, 1996; p. 360. [Google Scholar]
  78. Shakoor, M.B.; Nawaz, R.; Hussain, F.; Raza, M.; Ali, S.; Rizwan, M.; Oh, S.-E.; Ahmad, S. Human health implications, risk assessment and remediation of arsenic-contaminated water: A critical review. Sci. Total Environ. 2017, 601–602, 756–769. [Google Scholar] [CrossRef] [PubMed]
  79. Ciminelli, V.S.T.; Gasparon, M.; Ng, J.C.; Silva, G.C.; Caldeira, C.L. Dietary arsenic exposure in Brazil: The contribution of rice and beans. Chemosphere 2017, 168, 996–1003. [Google Scholar] [CrossRef] [PubMed]
  80. Yokel, R.A. Manganese flux across the blood-brain barrier. Neuromol. Med. 2009, 11, 297–310. [Google Scholar] [CrossRef] [PubMed]
  81. Schmitt, C.; Strazielle, N.; Richaud, P.; Bouron, A.; Ghersi-Egea, J.F. Active transport at the blood-CSF barrier contributes to manganese influx into the brain. J. Neurochem. 2011, 117, 747–756. [Google Scholar] [CrossRef] [PubMed]
  82. World Health Organization (Ed.) Concise International Chemical Assessment Document 63. In Manganese and Its Compounds: Environmental Aspects; World Health Organization: Geneva, Switzerland, 2004; p. 65. Available online: http://www.inchem.org/pages/cicads (accessed on 29 November 2017).
  83. Simms, J.A. Dark side of manganese. Chem. Eng. News 2011, 89, 4. [Google Scholar]
  84. Ritter, S.K. Study fuels toxicity debate. Chem. Eng. News 2014, 92, 40–41. [Google Scholar]
  85. Bouchard, M.F.; Sauve, S.; Barbeau, B.; Legrand, M.; Brodeur, M.-E.; Bouffard, T.; Limoges, E.; Bellinger, D.C.; Mergler, D. Intellectual impairment in school-age children exposed to manganese from drinking water. Environ. Health Perspect. 2011, 119, 138–143. [Google Scholar] [CrossRef] [PubMed]
  86. Al Saggaf, S.M.; Abdel-Hamid, G.A.; Hagras, M.; Saleh, H.A. Does selenium ameliorate toxic effects of prenatal aluminum on brain of full term rat fetuses? J. Anim. Vet. Adv. 2012, 11, 3588–3592. [Google Scholar]
  87. Lakshmi, B.V.S.; Sudhakar, M.; Prakash, K.S. Protective effect of selenium against aluminum chloride-induced Alzheimer’s disease: Behavioral and biochemical alterations in rats. Biol. Trace Elem. Res. 2015, 165, 67–74. [Google Scholar] [CrossRef] [PubMed]
  88. Gailer, J. Arsenic-selenium and mercury-selenium bonds in biology. Coord. Chem. Rev. 2007, 251, 234–254. [Google Scholar] [CrossRef]
  89. Wang, M.; Fu, H.; Xiao, Y.; Ai, B.; Wei, Q.; Wang, S.; Liu, T.; Ye, L.; Hu, Q. Effects of low-level organic selenium on lead-induced alterations in neural cell adhesion molecules. Brain Res. 2013, 1530, 76–81. [Google Scholar] [CrossRef] [PubMed]
  90. Yang, X.; Bao, Y.-X.; Fu, H.-H.; Li, L.-L.; Ren, T.-H.; Yu, X.-D. Selenium protects neonates against neurotoxicity from prenatal exposure to manganese. PLoS ONE 2014, 9, e86611. [Google Scholar] [CrossRef] [PubMed]
  91. Choi, A.L.; Budtz-Jorgensen, E.; Jorgensen, P.J.; Steuerwald, U.; Debes, F.; Weihe, P.; Grandjean, P. Selenium as a protective factor against mercury developmental neurotoxicity. Environ. Res. 2008, 107, 45–52. [Google Scholar] [CrossRef] [PubMed]
  92. Sakamoto, M.; Yasutake, A.; Kakita, A.; Ryufuku, M.; Chan, H.M.; Yamamoto, M.; Oumi, S.; Kobayashi, S.; Watanabe, C. Selenomethionine protects against neuronal degeneration by methylmercury in the developing rat cerebrum. Environ. Sci. Technol. 2013, 47, 2862–2868. [Google Scholar] [CrossRef] [PubMed]
  93. Schrauzer, G.N.; Surai, P.F. Selenium in human and animal nutrition: Resolved and unresolved issues. A partly historical treatise in commemoration of the 50th anniversary of the discovery of the biological essentiality of selenium, dedicated to the memory of Klaus Schwartz (1914–1978) on the occasion of the 30th anniversary of his death. Crit. Rev. Biotechnol. 2009, 29, 2–9. [Google Scholar] [CrossRef] [PubMed]
  94. Rayman, M.P. Selenium and human health. Lancet 2012, 379, 1256–1268. [Google Scholar] [CrossRef]
  95. Risher, J. Toxicological Profile for Selenium; Agency for Toxic Substances and Disease Registry: Atlanta, GA, USA, 2003; p. 457. Available online: http://www.atsdr.cdc.gov/ (accessed on 29 November 2017).
  96. Cesbron, A.; Saussereau, E.; Mahieu, L.; Couland, I.; Guerbet, M.; Goulle, J.-P. Metallic profile of whole blood and plasma in a series of 106 healthy volunteers. J. Anal. Toxicol. 2013, 37, 401–405. [Google Scholar] [CrossRef] [PubMed]
  97. Curren, M.S.; Liang, C.L.; Davis, K.; Kandola, K.; Brewster, J.; Potyrala, M.; Chan, H.M. Assessing determinants of maternal blood concentrations for persistent organic pollutants and metals in the Eastern and Western Canadian Arctic. Sci. Total Environ. 2015, 527, 150–158. [Google Scholar] [CrossRef] [PubMed]
  98. Tomljenovic, L.; Shaw, C.A. Aluminum vaccine adjuvants: Are they safe? Curr. Med. Chem. 2011, 18, 2630–2637. [Google Scholar] [CrossRef] [PubMed]
  99. Exley, C. What is the risk of aluminum as a neurotoxin? Expert Rev. Neurother. 2014, 14, 589–591. [Google Scholar] [CrossRef] [PubMed]
  100. Akay, C.; Kalman, S.; Dundaroz, R.; Sayal, A.; Aydin, A.; Ozkan, Y.; Gul, H. Serum aluminum levels in glue-sniffer adolescent and in glue containers. Basic Clin. Pharmacol. Toxicol. 2008, 102, 433–436. [Google Scholar] [CrossRef] [PubMed]
  101. Dong, Z.; Bank, M.S.; Spengler, J.D. Assessing metal exposures in a community near a cement plant in the northeast U.S. Int. J. Environ. Res. Public Health 2015, 12, 952–969. [Google Scholar] [CrossRef] [PubMed]
  102. Jung, E.; Hyun, W.; Ro, Y.; Lee, H.; Song, K. A study on blood lipid profiles, aluminum and mercury levels in college students. Nutr. Res. Pract. 2016, 10, 442–447. [Google Scholar] [CrossRef] [PubMed]
  103. Nisse, C.; Tagne-Fotso, R.; Howsam, M.; Richeval, C.; Labat, L.; Leroyer, A. Blood and urinary levels of metals and metalloids in the general adult population of Northern France: The IMEPOGE study, 2008–2010. Int. J. Hyg. Environ. Health 2017, 220, 341–363. [Google Scholar] [CrossRef] [PubMed]
  104. Birgisdottir, B.E.; Knutsen, H.K.; Haugen, M.; Gjelstad, I.M.; Jenssen, M.T.S.; Ellingsen, D.G.; Thomassen, Y.; Alexander, J.; Meltzer, H.M.; Brantsaeter, A.L. Essential and toxic element concentrations in blood and urine and their association with diet: Results from a Norwegian population study including high-consumers of seafood and game. Sci. Total Environ. 2013, 463/464, 836–844. [Google Scholar] [CrossRef] [PubMed]
  105. George, C.M.; Gamble, M.; Slavkovich, V.; Levy, D.; Ahmed, A.; Ahsan, H.; Graziano, J. A cross-sectional study of the impact of blood selenium on blood and urinary arsenic concentrations in Bangladesh. Environ. Health 2013, 12, 7. [Google Scholar] [CrossRef] [PubMed]
  106. Freire, C.; Koifman, R.J.; Fujimoto, D.; de Oliveira Souza, V.C.; Barbosa, F.B., Jr.; Koifman, S. Reference values of cadmium, arsenic and manganese in blood and factors associated with exposure levels among adult population of Rio Branco, Acre, Brazil. Chemosphere 2015, 128, 70–78. [Google Scholar] [CrossRef] [PubMed]
  107. Abass, K.; Koiranen, M.; Mazej, D.; Tratnik, J.S.; Horvat, M.; Hakkola, J.; Jarvelin, M.-R.; Rautio, A. Arsenic, cadmium, lead and mercury levels in blood of Finnish adults and their relation to diet, lifestyle habits and sociodemographic variations. Environ. Sci. Pollut. Res. 2017, 24, 1347–1362. [Google Scholar] [CrossRef] [PubMed]
  108. Kuno, R.; Roquetti, M.H.; Becker, K.; Seiwert, M.; Gouveia, N. Reference values for lead, cadmium and mercury in the blood of adults from the metropolitan area of Sao Paulo, Brazil. Int. J. Hyg. Environ. Health 2013, 216, 243–249. [Google Scholar] [CrossRef] [PubMed]
  109. Obiri, S.; Yeboah, P.O.; Osae, S.; Adu-Kumi, S. Levels of arsenic, mercury, cadmium, copper, lead, zinc and manganese in serum and whole blood of resident adults from mining and non-mining communities in Ghana. Environ. Sci. Pollut. Res. 2016, 23, 16589–16597. [Google Scholar] [CrossRef] [PubMed]
  110. Santos-Burgoa, C.; Rios, C.; Mercado, L.A.; Arechiga-Serrano, R.; Cano-Valle, F.; Eden-Wynter, R.A.; Texcalac-Sangrador, J.L.; Villa-Barragan, J.P.; Rodriguez-Agudelo, Y.; Montes, S. Exposure to manganese: Health effects on the general population, a pilot study in Central Mexico. Environ. Res. A 2001, 85, 90–104. [Google Scholar] [CrossRef] [PubMed]
  111. Bocca, B.; Madeddu, R.; Asara, Y.; Tolu, P.; Marchal, J.A.; Forte, G. Assessment of reference ranges for blood Cu, Mn, Se, and Zn in a selected Italian population. J. Trace Elem. Med. Biol. 2011, 25, 19–26. [Google Scholar] [CrossRef] [PubMed]
  112. Oulhote, Y.; Mergler, D.; Bouchard, M.F. Sex and age differences in blood manganese levels in the U.S. general population: National health and nutrition examination survey, 2011–2012. Environ. Health 2014, 13, 10. [Google Scholar] [CrossRef] [PubMed]
  113. McKelvey, W.; Gwynn, R.C.; Jeffery, N.; Kass, D.; Thorpe, L.E.; Garg, R.K.; Palmer, C.D.; Parsons, P.J. A biomonitoring study of lead, cadmium, and mercury in the blood of New York City Adults. Environ. Health Perspect. 2007, 115, 1435–1441. [Google Scholar] [CrossRef] [PubMed]
  114. Jain, R.B.; Choi, Y.S. Normal reference ranges for and variability in the levels of blood manganese and selenium by gender, age and race/ethnicity for general U.S. population. J. Trace Elem. Med. Biol. 2015, 30, 145–152. [Google Scholar] [CrossRef] [PubMed]
  115. Schulz, C.; Angerer, J.; Ewers, U.; Heudorf, U.; Wilhelm, M. Revised and new reference values for environmental pollutants in urine or blood of children in Germany derived from the German Environmental Survey on Children, 2003–2006 (GerES IV). Int. J. Hyg. Environ. Health 2009, 212, 637–647. [Google Scholar] [CrossRef] [PubMed]
  116. Interpretive Handbook—Mayo Medical Laboratories. 2015. Available online: https://www.mayomedicallaboratories.com/test-catalog/print-catalog.html?classification=interpretive (accessed on 29 November 2017).
  117. Environmental and Clinical Laboratory/Micro Trace Minerals Laboratory. Mineral Analysis: Whole Blood; Micro Trace Minerals: Boulder, CO, USA, 2012. [Google Scholar]
  118. Edwards, M. Fetal death and reduced birth rates associated with exposure to lead-contaminated drinking water. Environ. Sci. Technol. 2014, 48, 739–746. [Google Scholar] [CrossRef] [PubMed]
  119. Prokopowicz, A.; Pawlas, N.; Ochota, P.; Szula, M.; Sobczak, A.; Pawlas, K. Blood levels of lead, cadmium and mercury in healthy women in their 50s in an urban area of Poland: A pilot study. Pol. J. Environ. Stud. 2014, 23, 167–175. [Google Scholar]
  120. Hightower, J.M.; Moore, D. Mercury levels in high-end consumers of fish. Environ. Health Perspect. 2003, 111, 604–608. [Google Scholar] [CrossRef] [PubMed]
  121. Callan, A.C.; Hinwood, A.L.; Ramalingam, M.; Boyce, M.; Heyworth, J.; McCafferty, P.; Odland, J.O. Maternal exposure to metals: Concentrations and predictors of exposure. Environ. Res. 2013, 126, 111–117. [Google Scholar] [CrossRef] [PubMed]
  122. Rahbar, M.H.; Samms-Vaughan, M.; Dickerson, A.S.; Hessabi, M.; Bressler, J.; Desai, C.C.; Shakespeare-Pellington, S.; Reece, J.-A.; Morgan, R.; Loveland, K.A.; et al. Concentration of lead, mercury, cadmium, aluminum, arsenic and manganese in umbilical cord blood of Jamaican newborns. Int. J. Environ. Res. Public Health 2015, 12, 4481–4501. [Google Scholar] [CrossRef] [PubMed]
  123. Sanders, A.P.; Flood, K.; Chiang, S.; Herring, A.H.; Wolf, L.; Fry, R.C. Towards prenatal biomonitoring in North Carolina: Assessing arsenic, cadmium, mercury and lead levels in pregnant women. PLoS ONE 2012, 7, e31354. [Google Scholar] [CrossRef] [PubMed]
  124. Miklavcic, A.; Casetta, A.; Tratnik, J.S.; Mazej, D.; Krsnik, M.; Mariuz, M.; Sofianou, K.; Spiric, Z.; Barbone, F.; Horvat, M. Mercury, arsenic and selenium exposure levels in relation to fish consumption in the Mediterranean area. Environ. Res. 2013, 120, 7–17. [Google Scholar] [CrossRef] [PubMed]
  125. Baeyens, W.; Vrijens, J.; Gao, Y.; Croes, K.; Schoeters, G.; Hond, E.D.; Sioen, I.; Bruckers, L.; Nawrot, T.; Nelen, V.; et al. Trace metals in blood and urine of newborn/mother pairs, adolescents and adults of the Flemish population (2007–2011). Int. J. Hyg. Environ. Health 2014, 217, 878–890. [Google Scholar] [CrossRef] [PubMed]
  126. Al-Saleh, I.; Shinwari, N.; Mashhour, A.; Rabah, A. Birth outcome measures and maternal exposure to heavy metals (lead, cadmium and mercury) in Saudi Arabian population. Int. J. Hyg. Environ. Health 2014, 217, 205–218. [Google Scholar] [CrossRef] [PubMed]
  127. Sun, H.; Chen, W.; Wang, D.; Jin, Y.; Chen, X.; Xu, Y. The effects of prenatal exposure to low-level cadmium, lead and selenium on birth outcomes. Chemosphere 2014, 108, 33–39. [Google Scholar] [CrossRef] [PubMed]
  128. Ettinger, A.S.; Roy, A.; Amarasiriwardena, C.J.; Smith, D.; Lupoli, N.; Mercado-Garcia, A.; Lamadrid-Figueroa, H.; Tellez-Rojo, M.M.; Hu, H.; Hernandez-Avila, M. Maternal blood, plasma, and breast milk: Lactational transfer and contribution to infant exposure. Environ. Health Perspect. 2014, 122, 87–92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  129. Kim, Y.-M.; Chung, J.-Y.; An, H.S.; Park, S.Y.; Kim, B.-G.; Bae, J.W.; Han, M.; Cho, Y.J.; Hong, Y.-S. Biomonitoring of lead, cadmium, total mercury and methylmercury levels in maternal blood and in umbilical cord blood at birth in South Korea. Int. J. Environ. Res. Public Health 2015, 12, 13482–13493. [Google Scholar] [CrossRef] [PubMed]
  130. Gunier, R.B.; Mora, A.M.; Smith, D.; Arora, M.; Austin, C.; Eskenazi, B.; Bradman, A. Biomarkers of manganese exposure in pregnant women and children living in an agricultural community in California. Environ. Sci. Technol. 2014, 48, 14695–14702. [Google Scholar] [CrossRef] [PubMed]
  131. Chen, L.; Ding, G.; Gao, Y.; Wang, P.; Shi, R.; Huang, H.; Tian, Y. Manganese concentrations in maternal-infant blood and birth weight. Environ. Sci. Pollut. Res. 2014, 21, 6170–6175. [Google Scholar] [CrossRef] [PubMed]
  132. Arbuckle, T.E.; Liang, C.L.; Morisset, A.-S.; Fisher, M.; Weiler, H.; Cirtiu, C.M.; Legrand, M.; Davis, K.; Ettinger, A.S.; Fraser, W.D. Maternal and fetal exposure to cadmium, lead, manganese and mercury: The MIREC study. Chemosphere 2016, 163, 270–282. [Google Scholar] [CrossRef] [PubMed]
  133. Kozikowska, I.; Binkowski, L.J.; Szczepanska, K.; Slawska, H.; Miszczuk, K.; Sliwinska, M.; Laciak, T.; Stawarz, R. Mercury concentrations in human placenta, umbilical cord, cord blood and amniotic fluid and their relations with body parameters of newborns. Environ. Pollut. 2013, 182, 256–262. [Google Scholar] [CrossRef] [PubMed]
  134. Basu, N.; Tutino, R.; Zhang, Z.; Cantonwine, D.E.; Goodrich, J.M.; Somers, E.C.; Rodriguez, L.; Schnaas, L.; Solano, M.; Mercado, A.; et al. Mercury levels in pregnant women, children and seafood from Mexico City. Environ. Res. 2014, 135, 63–69. [Google Scholar] [CrossRef] [PubMed]
  135. Al-Saleh, I.; Abduljabber, M.; Al-Rouqi, R.; Eltabache, C.; Al-Rajudi, T.; Elkhatib, R.; Nester, M. The extent of mercury (Hg) exposure among Saudi mothers and their respective infants. Environ. Monit. Assess. 2015, 187, 29. [Google Scholar] [CrossRef] [PubMed]
  136. Lemire, M.; Kwan, M.; Laouan-Sidi, A.E.; Muckle, G.; Pirkle, C.; Ayotte, P.; Dewailly, E. Local country food sources of methylmercury, selenium and omega-3 fatty acids in Nunavik, Northern Quebec. Sci. Total Environ. 2015, 509–510, 248–259. [Google Scholar] [CrossRef] [PubMed]
  137. Taylor, C.M.; Golding, J.; Emond, A.M. Lead, cadmium and mercury levels in pregnancy: The need for international consensus on levels of concern. J. Dev. Origins Health Dis. 2014, 5, 16–30. [Google Scholar] [CrossRef] [PubMed]
  138. Gundacker, C.; Frohlich, S.; Graf-Rohrmeister, K.; Eibenberger, B.; Jessenig, V.; Gicic, D.; Prinz, S.; Wittmann, K.J.; Zeisler, H.; Vallant, B.; et al. Perinatal lead and mercury exposure in Austria. Sci. Total Environ. 2010, 408, 5744–5749. [Google Scholar] [CrossRef] [PubMed]
  139. Aylward, L.L.; Hays, S.M.; Kirman, C.R.; Marchitti, S.A.; Kenneke, J.F.; English, C.; Mattison, D.R.; Becker, R.A. Relationships of chemical concentrations in maternal and cord blood: A review of available data. J. Toxicol. Environ. Health B 2014, 17, 175–203. [Google Scholar] [CrossRef] [PubMed]
  140. Yokel, R.A. Toxicity of gestational aluminum exposure to the maternal rabbit and offspring. Toxicol. Appl. Pharmacol. 1985, 79, 121–133. [Google Scholar] [CrossRef]
  141. Kruger, P.C.; Schell, L.M.; Stark, A.D.; Parsons, P.J. A study of the distribution of aluminum in human placental tissues based on alkaline solubilization with determination by electrothermal atomic absorption spectrometry. Metallomics 2010, 2, 621–627. [Google Scholar] [CrossRef] [PubMed]
  142. Brown, I.A.; Austin, D.W. Maternal transfer of mercury to the developing embryo/fetus: Is there a safe level? Toxicol. Environ. Chem. 2012, 94, 1610–1627. [Google Scholar] [CrossRef]
  143. Ollson, C.J.; Smith, E.; Herde, P.; Juhasz, A.L. Influence of co-contaminant exposure on the absorption of arsenic, cadmium and lead. Chemosphere 2017, 168, 658–666. [Google Scholar] [CrossRef] [PubMed]
  144. Cobbina, S.J.; Chen, Y.; Zhou, Z.-X.; Wu, X.; Feng, W.; Wang, W.; Mao, G.; Xu, H.; Zhang, Z.; Wu, X.; et al. Low concentration toxic metal mixture interactions: Effects on essential and non-essential metals in brain, liver, and kidneys of mice on sub-chronic exposure. Chemosphere 2015, 132, 79–86. [Google Scholar] [CrossRef] [PubMed]
  145. Andrade, V.; Mateus, M.L.; Batoreu, M.C.; Aschner, M.; dos Santos, A.P.M. Urinary delta-ALA: A potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganese. Neurotoxicology 2013, 38, 33–41. [Google Scholar] [CrossRef] [PubMed]
  146. Karri, V.; Schuhmacher, M.; Kumar, V. Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: A general review of metal mixture mechanism in brain. Environ. Toxicol. Pharmacol. 2016, 48, 203–213. [Google Scholar] [CrossRef] [PubMed]
  147. McKelvey, S.M.; Horgan, K.A.; Murphy, R.A. Chemical form of selenium differentially influences DNA repair pathways following exposure to lead nitrate. J. Trace Elem. Med. Biol. 2015, 29, 151–169. [Google Scholar] [CrossRef] [PubMed]
  148. Folven, K.I.; Glover, C.N.; Malde, M.K.; Lundebye, A.-K. Does selenium modify neurobehavioral impacts of developmental methylmercury exposure in mice? Environ. Toxicol. Pharmacol. 2009, 28, 111–119. [Google Scholar] [CrossRef] [PubMed]
  149. Raymond, L.J.; Ralston, N.V.C. Selenium prevents and reverses methylmercury toxicity. Neurotoxicology 2006, 27, 1172–1173. [Google Scholar]
  150. Ralston, N.V.C.; Ralston, C.R.; Raymond, L.J. Selenium health benefit values: Updated criteria for mercury risk assessments. Biol. Trace Elem. Res. 2016, 171, 262–269. [Google Scholar] [CrossRef] [PubMed]
  151. Cusack, L.K.; Eagles-Smith, C.; Harding, A.K.; Kile, M.; Stone, D. Selenium: Mercury molar ratios in freshwater fish in the Columbia River basin: Potential applications for specific fish consumption advisories. Biol. Trace Elem. Res. 2017, 178, 136–146. [Google Scholar] [CrossRef] [PubMed]
  152. Meplan, C. Selenium and chronic diseases: A nutritional genomics. Nutrients 2015, 7, 3621–3651. [Google Scholar] [CrossRef] [PubMed]
  153. Dominiak, A.; Wilkaniec, A.; Wrocynski, P.; Adamczyk, A. Selenium in the therapy of neurological diseases. Where is it going? Curr. Neuropharmacol. 2016, 14, 282–299. [Google Scholar] [CrossRef] [PubMed]
  154. Pieczynska, J.; Grajeta, H. The role of selenium in human conception and pregnancy. J. Trace Elem. Med. Biol. 2015, 29, 31–38. [Google Scholar] [CrossRef] [PubMed]
  155. Cardoso, B.R.; Bandeira, V.S.; Jacob-Filho, W.; Cozzolino, S.M.F. Selenium status in elderly: Relation to cognitive decline. J. Trace Elem. Med. Biol. 2014, 28, 422–426. [Google Scholar] [CrossRef] [PubMed]
  156. Alehagen, U.; Alexander, J.; Aaseth, J. Supplementation with selenium and co-enzyme Q10 reduces cardiovascular mortality in elderly with low selenium status. A secondary analysis of a randomized clinical trial. PLoS ONE 2016, 11, e0157541. [Google Scholar] [CrossRef] [PubMed]
  157. Alehagen, U.; Johansson, P.; Aaseth, J.; Alexander, J.; Wagsater, D. Significant changes in circulating microRNA by dietary supplementation of selenium and co-enzyme Q10 in healthy elderly males. A subgroup analysis of a prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. PLoS ONE 2017, 12, e174880. [Google Scholar] [CrossRef]
  158. Cardoso, B.R.; Roberts, B.R.; Bush, A.I.; Hare, D.J. Selenium, selenoproteins and neurodegenerative diseases. Metallomics 2015, 7, 1213–1228. [Google Scholar] [CrossRef] [PubMed]
  159. Solovyev, N.D. Importance of selenium and selenoprotein for brain function: From antioxidant protection to neuronal signaling. J. Inorg. Biochem. 2015, 153, 1–12. [Google Scholar] [CrossRef] [PubMed]
  160. Du, X.-B.; Wang, C.; Liu, Q. Potential roles of selenium and selenoproteins in the prevention of Alzheimer’s disease. Curr. Top. Med. Chem. 2016, 16, 835–848. [Google Scholar] [CrossRef] [PubMed]
  161. Cardoso, B.R.; Hare, D.J.; Lind, M.; McLean, C.A.; Volitakis, I.; Laws, S.M.; Masters, C.L.; Bush, A.I.; Roberts, B.R. The APOE epsilon 4 allene is associated with lower selenium levels in the brain: Implications for Alzheimer’s disease. Am. Chem. Soc. Chem. Neurosci. 2017, 8, 1459–1464. [Google Scholar] [CrossRef] [PubMed]
  162. Naziroglu, M.; Muhamad, S.; Pecze, L. Nanoparticles as potential clinical therapeutic agents in Alzheimer’s disease: Focus on selenium nanoparticles. Exp. Rev. Clin. Pharmacol. 2017, 10, 773–782. [Google Scholar] [CrossRef] [PubMed]
  163. Bjorklund, G.; Aaseth, J.; Ajsuvakova, O.P.; Nikonorov, A.A.; Skainy, A.V.; Skainaya, M.G.; Tinkov, A.A. Molecular interaction between mercury and selenium in neurotoxicity. Coord. Chem. Rev. 2017, 332, 30–37. [Google Scholar] [CrossRef]
  164. Schofield, K. Autism, chemicals, probable cause and mitigation: A new examination. Autism Open Access 2016, 6, 27. [Google Scholar] [CrossRef]
  165. Thakur, J.S.; Prinja, S.; Singh, D.; Rajwanshi, A.; Prasad, R.; Parwana, H.K.; Kumar, R. Adverse reproductive and child health outcomes among people living near highly toxic waste water drains in Punjab, India. J. Epidemiol. Community Health 2010, 64, 148–154. [Google Scholar] [CrossRef] [PubMed]
  166. Kim, I.; Kim, M.H.; Lim, S. Increased risk of spontaneous abortion and menstrual aberrations in female workers in semiconductor industry, South Korea. Occup. Environ. Med. 2014, 71 (Suppl. 1), A15. [Google Scholar] [CrossRef]
  167. Passini, R.P., Jr.; Cecatti, J.G.; Lajos, G.J.; Tedesco, R.P.; Nomura, M.L.; Dias, T.Z.; Haddad, S.M.; Rehder, P.M.; Pacagnella, R.C.; Costa, M.L.; et al. Brazilian multicenter study on preterm birth: Prevalence and factors associated with spontaneous preterm birth. PLoS ONE 2014, 9, e109069. [Google Scholar] [CrossRef] [PubMed]
  168. Amadi, C.N.; Igweze, Z.N.; Orisakwe, O.E. Heavy metals in miscarriages and stillbirths in developing nations. Middle East Fertil. Soc. J. 2017, 22, 91–100. [Google Scholar] [CrossRef]
  169. Klemm, L.; Scialli, A.R. The transport of chemicals in semen. Birth Defects Res. B Dev. Reprod. Toxicol. 2005, 74, 119–131. [Google Scholar] [CrossRef] [PubMed]
  170. Sengupta, P.; Banerjee, R.; Nath, S.; Das, S.; Banerjee, S. Metals and female reproductive toxicity. Hum. Exp. Toxicol. 2015, 34, 679–697. [Google Scholar] [CrossRef] [PubMed]
  171. Nenkova, G.; Petrov, L.; Alexandrova, A. Role of trace elements for oxidative status and quality of human sperm. Balk. Med. J. 2017, 34, 343–348. [Google Scholar] [CrossRef] [PubMed]
  172. DeLong, G. A positive association found between autism prevalence and childhood vaccination uptake across the US population. J. Toxicol. Environ. Health A 2011, 74, 903–916. [Google Scholar] [CrossRef] [PubMed]
  173. Goldman, G.S. Comparison of the vaccine adverse event reporting system (VAERS) fetal-loss reports during three consecutive influenza seasons: Was there a synergistic fetal toxicity associated with the two-vaccine 2009/2010 season? Hum. Exp. Toxicol. 2013, 32, 464–475. [Google Scholar] [CrossRef] [PubMed]
  174. Bjermo, H.; Sand, S.; Nalsen, C.; Lundh, T.; Barbieri, H.E.; Pearson, M.; Lindroos, A.K.; Jonsson, B.A.G.; Barregard, L.; Darnerud, P.O. Lead, mercury and cadmium in blood and their relation to diet among Swedish adults. Food Chem. Toxicol. 2013, 57, 161–169. [Google Scholar] [CrossRef] [PubMed]
  175. Laks, D.R. Mercury rising: Response to the EPA assessment of mercury exposure. Biometals 2014, 27, 1–4. [Google Scholar] [CrossRef] [PubMed]
  176. Gaskin, J.; Rennie, C.; Coyle, D. Reducing periconceptual methylmercury exposure: Cost-utility for a proposed screening program for women planning a pregnancy in Ontario, Canada. Environ. Health Perspect. 2015, 123, 1337–1344. [Google Scholar] [CrossRef] [PubMed]
  177. Bellinger, D.C.; O’Leary, K.; Rainis, H.; Gibb, H.J. Country specific estimates of the incidence of intellectual disability associated with prenatal exposure to methylmercury. Environ. Res. 2016, 147, 159–163. [Google Scholar] [CrossRef] [PubMed]
  178. Starling, P.; Charlton, K.; McMahon, A.T.; Lucas, C. Fish intake during pregnancy and foetal neurodevelopment: A systematic review of the evidence. Nutrients 2015, 7, 2001–2014. [Google Scholar] [CrossRef] [PubMed]
  179. Taylor, C.M.; Golding, J.; Emond, A.M. Blood mercury levels and fish consumption in pregnancy: Risks and benefits for birth outcomes in a prospective observational birth cohort. Int. J. Hyg. Environ. Health 2016, 219, 513–520. [Google Scholar] [CrossRef] [PubMed]
  180. Alves, J.C.; de Paiva, E.L.; Milani, R.F.; Bearzoti, E.; Morgano, M.A.; Quintaes, K.D. Risk estimation to human health caused by the mercury content of Sushi and Sashimi sold in Japanese restaurants in Brazil. J. Environ. Sci. Health B 2017, 52, 418–424. [Google Scholar] [CrossRef] [PubMed]
  181. Rose, M.; Baxter, M.; Brereton, N.; Baskaran, C. Dietary exposure to metals and other elements in the 2006 UK total diet study and some trends over the last 30 years. Food Addit. Contam. 2010, 27, 1380–1404. [Google Scholar] [CrossRef] [PubMed]
  182. Rescue, G. Autism and Vaccines around the World: Vaccine Schedules, Autism Rates and under 5 Mortality; Special Report; Generation Rescue, Inc.: Los Angeles, CA, USA, 2009; p. 4. [Google Scholar]
  183. Branco, V.; Caito, S.; Farina, M.; da Rocha, J.T.; Aschner, M.; Carvalho, C. Biomarkers of mercury toxicity: Past, present and future trends. J. Toxicol. Environ. Health B Crit. Rev. 2017, 20, 119–154. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Samples of blood concentration/percentage-distribution surveys for adult populations for the six neurotoxins. Approximate maximum values are given in parenthesis indicating the upper value extremes and tail lengths reported for outlier cases. Displayed values are taken from As [106]; Al [103]; Hg [107]; Mn [112]; Pb [103]; and Se [114].
Figure 1. Samples of blood concentration/percentage-distribution surveys for adult populations for the six neurotoxins. Approximate maximum values are given in parenthesis indicating the upper value extremes and tail lengths reported for outlier cases. Displayed values are taken from As [106]; Al [103]; Hg [107]; Mn [112]; Pb [103]; and Se [114].
Ijerph 14 01511 g001
Figure 2. Samples of blood concentration/percentage-distribution surveys of pregnant women for four of the neurotoxin metals. Approximate maximum values are given in parenthesis indicating the upper value extremes observed. Displayed values are taken from Hg [134,135]; Mn [130]; Pb [138]; and Se [127].
Figure 2. Samples of blood concentration/percentage-distribution surveys of pregnant women for four of the neurotoxin metals. Approximate maximum values are given in parenthesis indicating the upper value extremes observed. Displayed values are taken from Hg [134,135]; Mn [130]; Pb [138]; and Se [127].
Ijerph 14 01511 g002
Table 1. Typical average values and observed upper limits of the six neurotoxins monitored in blood samples in various adult population surveys, µg/L.
Table 1. Typical average values and observed upper limits of the six neurotoxins monitored in blood samples in various adult population surveys, µg/L.
MRLAverage (Maximum Value), Country
Al *<637 [100] Turkey4.6 (≤17) [101] USA7.1 [102] Korea4.3 (≤11.8) [103] France
As<121.9 (≤7.1) [96] France5.9 (≤41) [104] Norway7.0 (≤56) [105] Bangladesh4.1 (≤31) [106] Brazil0.8 (≤18) [107] Finland
Pb50–702.7 (≤131) [108] Brazil25 (≤65) [104] Norway2.4 (≤245) [109] Ghana23 (≤54) [103] France17 (≤146) [107] Finland
Mn<1818 (≤88) [110] Mexico8.9 (<17) [111] Italy9.9 (≤62) [112] USA13 (≤119) [106] Brazil1.5 (≤42) [109] Ghana
Hg<5.82.7 (≤36) [113] USA1.7 (≤5.1) [96] France4.0 (≤13) [104] Norway1.4 (≤12) [108] Brazil2.5 (≤15) [107] Finland
Se70–130110 (≤142) [96] France95 (≤153) [104] Norway123 (≤222) [105] Bangladesh190 (≤253) [114] USA104 (≤245) [107] Finland
MRL: Suggested minimum risk levels; specific references are in squared parentheses. * No reliable data are yet available containing vaccine effects.
Table 2. Typical average values and observed upper limits of the six neurotoxins monitored in blood samples from various pregnant women surveys, µg/L.
Table 2. Typical average values and observed upper limits of the six neurotoxins monitored in blood samples from various pregnant women surveys, µg/L.
MRLAverage (Maximum Value), Country
Al *<665 (≤860) [121] Australia11 (≤28) [122] Jamaica
As<120.4 (≤8.6) [123] USA1.9 (≤16) [121] Australia2.1 (≤37) [124] Croatia1.2 (≤33) [124] Italy0.6 (≤5.8) [125] Belgium
Pb<508.9 (≤77) [123] USA29 (≤260) [126] Saudi Arabia45 (≤137) [127] China77 (≤287) [128] Mexico10 (≤22) [129] South Korea
Mn<189.1 (≤50) [121] Australia15 (≤33) [130] USA12 (≤40) [125] Belgium66 (≤304) [131] China13 (≤34) [132] Canada
Hg<3.58.0 (≤16) [133] Poland2.4 (≤40) [124] Italy3.7 (≤31) [134] Mexico0.9 (≤49) [135] Saudi Arabia11 (≤241) [136] North Canada
Se70–130102 (≤374) [121] Australia117 (≤229) [124] Italy90 (≤182) [124] Croatia157 (≤456) [127] China271 (≤357) [136] North Canada
MRL: Minimum risk level (not clearly defined at all for pregnancy and the fetus). Specific references are in squared parentheses. * No reliable data are yet available containing vaccine effects.

Share and Cite

MDPI and ACS Style

Schofield, K. The Metal Neurotoxins: An Important Role in Current Human Neural Epidemics? Int. J. Environ. Res. Public Health 2017, 14, 1511. https://doi.org/10.3390/ijerph14121511

AMA Style

Schofield K. The Metal Neurotoxins: An Important Role in Current Human Neural Epidemics? International Journal of Environmental Research and Public Health. 2017; 14(12):1511. https://doi.org/10.3390/ijerph14121511

Chicago/Turabian Style

Schofield, Keith. 2017. "The Metal Neurotoxins: An Important Role in Current Human Neural Epidemics?" International Journal of Environmental Research and Public Health 14, no. 12: 1511. https://doi.org/10.3390/ijerph14121511

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop