FAN Bulletin
November 13, 2006

Protecting the brain or the teeth?

by Paul Connett, PhD

I am sure that many of you have seen press accounts of the important paper which was published last week in The Lancet, the premier medical journal in the UK. The article dealt with the impact of chemicals on fetal, infant and child brain development. Some press reports included a reference to the short section on fluoride (The Times of London) and others did not (Associated Press). This article is so important in my view, that I have copied out the bulk of it below. Even in this shortened version it is long, but it is well worth the time to read through this carefully.

This article is extremely important on several fronts, including our battles against both water fluoridation and the use of sulfuryl fluoride as a fumigant on food in warehouses.

The authors, Philippe Grandjean & Philip Landrigan, have stuck their necks out and discussed the large universe of chemicals which may impact the developing brain, not just one or two specific chemicals. The main point of their review is that of the thousands of potentially neurotoxic chemicals for kids, only a very small percentage have been tested in animals, and an even smaller percentage have been investigated in humans.

Human studies have usually started with high level occupational or accidental exposures among adults. Thereupon people have wondered whether lower levels might also affect children. Of the known developmental neurotoxins (DNT), all of them have been established very gradually, starting first with animal studies, or studies on adult humans, and then – finally - children. Thus, proving a chemical can damage a child’s developing brain in this way can take many years (e.g lead) and in the intervening years, may lead to millions of children being unnecessarily exposed. The authors suggest there is the potential for many more DNTs and point out that the vast majority of chemicals have not even been examined at the first level: animal tests.

This background makes The Lancet review’s discussion of fluoride even more important, because the authors single it out as one of the few which has been examined minimally (in both animals and humans) with the studies thus far indicating it has neurotoxic effects.

Their analogies to the "headliners" of lead, mercury, PCBs (dioxins), and arsenic are also worth discussing. Basically, the authors are suggesting that fluoride may be next in line (they describe it as an “emerging neurotoxic substance”), but since it took so long to "prove" that lead was a developmental neurotoxin, it may also take a while to "prove" fluoride is as well.

(On a personal note I remember saying in a TV interview I gave on British TV in 1996 that I felt that fluoride, as far as brain damage was concerned, was where lead was in the 1970s.)

The bottom line is that Grandjean and Landrigan are invoking the "precautionary principle", but not just in a philosophical sense, but using hard evidence to show how our history of determining DNT suggests there is a very real possibility that chemicals like fluoride will be proven to cause DNT. To ignore and not act on this possibility is totally irresponsible. And by act, I mean either reduce exposure or immediately invest in high quality studies to determine whether it does or not. Right now in the US this is not being done. In fact, the very opposite is true. When Mullenix found a problem she was fired! What studies we have, therefore, come largely from overseas, particularly China.

In other fluoridating countries, such as Australia, Ireland, New Zealand, no serious fluoride research is being carried out on the brain or any other tissue except the teeth. In the UK, the MRC in 2002 recommended a higher priority for fluoride research on dental fluorosis than on its impacts on the brain! The MRC even dismissed the need to pursue fluoride’s impacts on the pineal gland, even though this research was carried out right under their noses by British researcher Jennifer Luke (1997, 2001).

While we were pleased to see The Lancet’s review refer to a few of the studies on fluoride and the brain, they only viewed the tip of the iceberg. We have repeatedly drawn attention to the fact that over 30 animal studies indicate that fluoride can cause brain damage (and some at very low levels, e.g. Varner 1998), as well as the several studies from China which indicate that naturally occurring fluoride lowers IQ at relatively low levels (1.8 ppm, Xiang, 2003) and at even lower levels if the child has an iodine deficiency (0.9 ppm, Lin Fa-Fu 1991). Research from China has also found that elevated fluoride exposure among pregnant mothers damages the brain of the fetus (Du 1992). Most of these studies were reviewed by the recent NAS panel (NRC, 2006).

Unfortunately, The Lancet review draws attention to only four studies (Mullenix et al., 1995; Xiang et al., 2003; Lu et al, 2000 and Qin et al.,1990) and leaves the impression that these effects only occur at high fluoride levels. But at least they have broken the ice. The mainstream medical journals hardly mention the issue at all.

This review of the potential for fluoride to interfere with fetal and infant brain development (limited as it was) brings us back, with an increased urgency, to the last bulletin which dealt with the ADA’s advice (very slow in coming) that infants should not be given formula made up with fluoridated tap water.

The ADA’s major concern is the dramatic increase in the occurrence of dental fluorosis among American children. With 32% of children now impacted -- a 9% increase from the rate in the 1980s (CDC, 2005) -- this is hard for even the most pro-fluoridation diehard to deny. But as fluoridation critics have pointed out many times, dental fluorosis is only the first VISIBLE sign of fluoride’s toxic effect on the body. We have to worry about what other less visible and subtle systemic (and largely unstudied) effects may also be occurring commensurate with damage to the growing tooth cells. The National Research Council (2006) report reviewed the evidence that fluoride may have direct impacts on the brain (there are many possible mechanisms, reviewed as long ago as 1994 by Bruce Spittle), and indirect effects through both lowering of thyroid function (exacerbated by iodine deficiency) and accumulation in the pineal gland (Luke, 1997, 2001).

The ADA’s statement on advising parents not to use fluoridated tap water for infant formula was largely ignored by the media. Now that The Lancet has made visible the potential for fluoride to impact the developing brain, this gives even greater reason for the ADA advice to be recognized and heeded. After all, isn’t the baby’s developing brain more important than its developing teeth?

Thus, inadvertently the ADA, and the FDA (which has recently ruled that claims of fluoridated water’s benefits can not be targeted to infants), and the Lancet review, have provided fresh impetus for halting water fluoridation IMMEDIATELY. Why? Because even if the ADA and others tried very hard – and there is no indication that they will - their recommendation that infants should not drink fluoridated water will not reach millions of American parents who will continue to use tap water to make up formula, oblivious to its real and potential dangers. It would make far more sense and be far more effective to abandon this shortsighted policy than to embark on an educational campaign to reach the whole population of nursing mothers. It is one thing if this contributes to dental fluorosis, it is quite another if it leads to further brain development problems (subtle as they may be) in our children. Unlike the accidental and localized exposure that some children have to industrial chemicals, millions of children get deliberately and unnecessarily exposed to this chemical every day in their drinking water. As Grandjean and Landrigan make clear for lead, a slight shift in IQ for a whole population has a devastating effect on the number of children with very high and very low IQs, with untold costs to society at large. Urgent action is of paramount importance.

Again, Nature said it first. The level in mothers milk is 250 times lower than that added to water (0.004 ppm versus 1 ppm). It is time to acknowledge that Nature may know a great deal more about what the baby needs - and what may be dangerous for the baby’s brain - than the zealots who continue to promote this practice at the ADA, and the CDC (as well as those who are neglecting their duty on this matter at the FDA). If ever an entity gave a sound foundation for exercising the precautionary principle it must be the guidebook that nature provided in baby’s first meal. A meal consumed at a time when, as Grandjean and Landrigan clearly illustrate in the Lancet article, the developing brain is most vulnerable to neurotoxins.

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The Developmental neurotoxicity of industrial chemicals

P Grandjean, PJ Landrigan

Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.

One in every six children has a developmental disability and in most cases these disabilities affect the nervous system. 1 The most common neurodevelopmental disorders include learning disabilities, sensory deficits, developmental delays, and cerebral palsy. 1 Some experts have reported that the prevalence of certain neurodevelopmental disorders— autism and attention deficit and hyperactivity disorder, in particular—might be increasing, but there are few data to sustain that position. 2 Treatment of these disorders is difficult, and the disabilities they cause can be permanent; 3 they are therefore very costly to families and to society. 4–6

Evidence has been accumulating over several decades that industrial chemicals can cause neurodevelopmental damage and that subclinical stages of these disorders might be common. The possibility of a link between chemicals and widespread neurobehavioural changes was first raised by research showing that lead was toxic to the developing brain across a wide range of exposures. 7–10 That report was in accord with reports indicating that other environmental pollutants were also toxic to early brain development. 11 An expert committee from the US National Research Council concluded that 3% of developmental disabilities are the direct result of environmental exposure to such substances, and that another 25% arise through interactions between environmental factors and individual genetic susceptibility. 3 These estimates were based on scarce information about neurotoxicity and could therefore underestimate the true prevalence of chemically-induced abnormalities.

Neurobehavioural damage caused by industrial chemicals is, in theory, preventable. An essential prerequisite to prevention is recognition of a chemical’s ability to harm the developing brain. Knowledge that a chemical is neurotoxic can prompt efforts to restrict its use and to control exposure. Previous evidence-based programmes of exposure prevention, such as those directed against children’s exposure to lead, have been highly successful, although they were initiated after substantial delay.

The aims of this review are to characterise the vulnerability of the developing nervous system to chemical toxicity; to collate publicly available data for human neurotoxicity of industrial chemicals; to examine the possible extent of a developmental neurotoxicity pandemic; to describe the known consequences of developmental neurotoxicity for individuals and society; to examine the implications for human health of the dearth of toxicological information; and to consider prospects for prevention of exposure.

Vulnerability of the developing brain

The developing human brain is inherently much more susceptible to injury caused by toxic agents than is the brain of an adult. 12 This susceptibility stems from the fact that during the 9 months of prenatal life, the human brain must develop from a strip of cells along the dorsal ectoderm of the fetus into a complex organ consisting of billions of precisely located, highly interconnected, and specialised cells. Optimum brain development requires that neurons move along precise pathways from their points of origin to their assigned locations, that they establish connections with other cells, both nearby and distant, and that they learn to communicate with other cells via such connections. 12–14 All these processes have to take place within a tightly controlled time frame, in which each developmental stage has to be reached on schedule and in the correct sequence. Because of the extraordinary complexity of human brain development, windows of unique susceptibility to toxic interference arise that have no counterpart in the mature brain, or in any other organ. If a developmental process in the brain is halted or inhibited, there is little potential for later repair, and the consequences can therefore be permanent. 12,14

During fetal development, the placenta offers some protection against unwanted chemical exposures, but it is not an effective barrier against environmental pollutants. 15 For example, many metals easily cross the placenta, and the mercury concentration in umbilical cord blood can be substantially higher than in maternal blood. 16 The blood-brain barrier, which protects the adult brain from many toxic chemicals, is not completely formed until about 6 months after birth. 17

The human brain continues to develop postnatally, and the period of heightened vulnerability therefore extends over many months, through infancy and into early childhood. Although most neurons have been formed by the time of birth, growth of glial cells and myelinisation of axons continues for several years. 13,14

The susceptibility of infants and children to industrial chemicals is further enhanced by their increased exposures, augmented absorption rates, and diminished ability to detoxify many exogenous compounds, relative to that of adults. 18,19 Persistent lipophilic substances, including specific pesticides and halogenated industrial compounds, such as PCBs, accumulate in maternal adipose tissue and are passed on to the infant via breast milk, resulting in infant exposure that exceeds the mother’s own exposure by 100-fold on the basis of bodyweight. 20

Recognition of neurotoxicity

Developmental neurotoxicity in children exposed to industrial chemicals is often first identified through recognition of obvious functional abnormalities after high-dose exposure that clearly caused poisoning. Good quality research later documented the presence of less striking, but nonetheless serious adverse effects at low doses of exposure (figure 1). This sequence of discovery led to the recognition that environmental pollutants exert a range of adverse effects—some are clinically evident, but others can be discerned only through special testing and are not evident on standard examination, hence the term subclinical toxicity. The underlying idea is that there is a dose-dependent continuum of toxic effects, in which clinically obvious effects have subclinical counterparts. 21 A pandemic of subclinical neurotoxicity is therefore likely to be silent—ie, not apparent from standard health statistics. The notion of subclinical toxicity originates from the pioneering work of Landrigan 7 Needleman 8 and their colleagues, which, showed that children’s exposure to lead could cause reductions in intelligence and changes in behaviour even in the absence of clinically visible symptoms of lead toxicity. The subclinical toxicity of lead in children has subsequently been confirmed in prospective epidemiological studies. 22,23

Parallel findings have been reported on some other industrial chemicals, but their number is small. About 80,000 chemicals are registered for commercial use with the US Environmental Protection Agency, and 62 000 were already in use when the Toxic Substances Control Act was enacted in the USA in 1977. 24 The situation is similar in the EU, where 100,000 chemicals were registered in 1981. 25 The full extent to which these chemicals contribute to neurodevelopmental disorders and subclinical neurotoxicity is still unknown.

Neurotoxic agents

Identification

Studies in animals support the notion that a wide range of industrial chemicals can cause developmental neurotoxicity at low doses that are not harmful to mature organisms. 26,27 Such injury seems to result in permanent changes in brain function that might become detectable only when the animal reaches maturity. Because developmental neurotoxicity might not be apparent from routine toxicology tests, 28 identification of neurotoxic chemicals often rests on clinical and epidemiological data.

To identify environmental chemicals that are toxic to the human brain, we searched the hazardous substances data bank of the US National Library of Medicine, where substances are listed with their adverse effects in human beings. We checked the completeness of this list against other data sources and with a previous review of published data for clinical toxicity. 29 The panel shows the industrial chemicals known to be neurotoxic in human beings. We have excluded drugs, food additives, microbial toxins, and snake venoms and similar biogenic substances. This list excludes chemicals that have proved neurotoxic solely in laboratory animals, for which no systematic list exists. We mainly include acutely toxic substances that have caused serious accidents or have been used in suicide attempts, Neurotoxins that mainly cause chronic or delayed disease are likely to be underrepresented. 29 The largest groups of identified compounds are metals, solvents, and pesticides, but other chemicals with less documentation could have unrecognised effects. The list therefore should not be regarded as comprehensive. These substance names (see panel) were used for searches of published data for developmental neurotoxicity. On the basis of our critical review, the few known chemicals causing neurodevelopmental abnormalities are highlighted in the panel. Many more chemicals that we have not listed are known to harm neurodevelopment in laboratory animals, 27 but no data about their potential toxic effects on human brain development are available.

(There follow sections on Lead, Methylmercury, Arsenic, Polychlorinated biphenyls, Solvents and Pesticides)

Emerging neurotoxic substances

Documentation of developmental effects in human beings for the other compounds listed in the panel is poor. However, three obvious candidate substances deserve particular attention, including two that have not seemed to cause neurotoxicity in adults.

Fluoride

Fluoride can cause neurotoxicity in laboratory animals, 89 but is not shown in the panel as a substance proven to be neurotoxic in man. It exists in drinking water as a natural contaminant, but the concentration is dependent on local geological circumstances. In rural communities in China, high fluoride concentrations in well water might cause skeletal abnormalities. In one such community, 222 children aged 8–13 years showed significantly worse IQs than 290 unexposed controls. 90 Parallel results were obtained in a smaller study of 118 children of similar age. 91 Another study of 477 schoolchildren from 22 villages suggested that both increased water fluoride concentrations and very low concentrations were associated with IQ deficits, compared with children exposed to normal concentrations (below 1 mg/L). 92 The reports did not thoroughly consider possible confounders, but do suggest that further in-depth studies be undertaken.

Effects of developmental neurotoxicity

The five substances recognised as causes of developmental neurotoxicity show similar patterns in the development of scientific documentation of their risks. This pattern of discovery started in each instance with recognition of adult neurotoxicity, typically in people with occupational exposure, and of episodes of acute, high-dose poisoning in children. The next stage was the accumulation of epidemiological evidence of neurobehavioural deficits in children with prenatal exposures at concentrations that are not toxic to adults (figure 1). For lead, methylmercury, and PCBs, widespread subclinical neurotoxicity has been documented internationally, yet the full implications of exposure to arsenic and toluene are unclear. For most substances listed in the panel, only neurotoxicity in adults has been documented.

The combined evidence suggests that neurodevelopmental disorders caused by industrial chemicals has created a silent pandemic in modern society. Although these chemicals might have caused impaired brain development in millions of children worldwide, the profound effects of such a pandemic are not apparent from available health statistics. Additionally, as shown by this Review, only a few chemical causes have been recognised so the full effects of our industrial activities could be substantially greater than recognised at present.

As is shown by the evidence for inorganic lead, globally increased exposures have been responsible for erosion of cognitive skills with subclinical, but permanent, decreases in IQ. Additionally, this neurotoxic chemical produces lifelong changes in behaviour with shortened attention span, increased impulsivity, heightened aggressiveness, slowed motor coordination, and impaired memory and language skills. The consequences are increased likelihood of school failure, diminished economic productivity, and possibly increased risk of antisocial and criminal behaviour. 94 The most striking of these effects occur at the extremes of performance; in highly exposed children, almost none had above average function, whereas the number with obvious deficits increased greatly. 95 The most severely affected individuals will probably need special education and will also be less likely than their peers to pursue productive career options. A study of adults who were exposed to excess lead as children revealed that they were much less successful in life than those from a less exposed comparison group. 96

The consequences of a pandemic of developmental neurotoxicity extend beyond descriptive data for incidence and prevalence of clinically diagnosed disorders. 1,3 Increased risk of Parkinson’s disease 97 or other neurodegenerative diseases 98 is a further potential consequence of the pandemic. Thus, early subclinical chemical injury has been postulated to silently kill a fraction of the cells needed to sustain brain function in later life (eg, in the substantia nigra). These latent impairments cause no symptoms in childhood, but could be unmasked during the natural neuronal attrition associated with ageing. 99,100

The wide extent of human exposure to pollutants is now becoming apparent after systematic collection of data for the amounts of these substances present in the environment and in human tissues. 101 However, recognition of causal associations could be difficult because exposures vary with time, more than one substance could have an effect, individual vulnerability varies, and other factors can bias epidemiological studies toward the null hypothesis, especially when the outcome might be unrecognised for several years, or even decades. 102

The population at risk of subclinical neurotoxicity from industrial chemicals is very large. Almost all children born in industrialised countries between 1960 and 1980 were exposed to substantial amounts of lead from petrol that could have reduced the number of children with far above average intelligence (IQ scores above 130 points) by over 50% and might likewise have increased the number with IQ scores below 70. 95 In the USA alone, the aggregate population of children at risk of exposure to airborne lead at that time was about 100 million. In this period, the resulting economic costs are estimated to have ranged from US$110 billion to $319 billion in each year’s birth cohort. 103 Most of these costs were related to the diminished economic productivity that resulted over the exposed children’s entire lifetimes from wide-scale reductions in intelligence. Today the costs of lead poisoning are estimated to be $43 billion in each birth cohort in the USA, 5 whereas the costs of prenatal methylmercury toxicity are estimated to amount to $8·7 billion yearly (range, $2·2–43·8 billion). 6 Diminished economic productivity remains the main source of these costs. Because of the absence of dose-response associations for other neurotoxic compounds, the total costs are unknown.

The effect of chemical neurotoxicity extends beyond the industrially developed nations. Toxic chemicals, such as highly dangerous pesticides that are banned in industrialised countries, are exported to developing societies, where environmental and occupational standards are often weak or at least poorly enforced. 104 The consequences are largely unreported.

Prevention

A pandemic of neurodevelopmental toxicity caused by industrial chemicals is, in theory, preventable. Testing of new chemicals before allowing them to be marketed is a highly efficient means to prevent toxicity, but has been required only in recent years. Of the thousands of chemicals used in commerce, fewer than half have been subjected to even token laboratory testing for toxicity testing. 24 Nearly 3000 of these substances are produced in quantities of almost 500 000 kg every year, but for nearly half these high-volume chemicals no basic toxicity data are publicly available, and 80% have no information about developmental or paediatric toxicity. 24 Although new chemicals must be tested more thoroughly, access to these data can be restricted, because they could be claimed to constitute confidential business information. Absence of information about the neurotoxic potential of most industrial chemicals is therefore the main impediment to prevention of developmental disorders induced by neurotoxic pollutants. Accelerated testing of chemicals already in commerce is therefore essential. In the USA, a legal mandate to require testing was established in the Toxic Substances Control Act, but is largely unenforced. 24 In the EU, opportunity exists to require more extensive chemical testing through the REACH programme, 25 although the proposed legislation does not emphasise testing for developmental neurotoxicity as a primary objective.

Toxicity testing protocols for chemicals need to be expanded to include examination of neurobehavioural functions. Present test protocols rely mainly on crude indices, such as brain weight and gross morphology. 105,106 There is a risk that abbreviated protocols used for toxicity screening will overlook neurodevelopmental toxicity, and further testing could erroneously be thought unnecessary. Procedures for functional appraisal are available, 105 and a harmonised protocol for assessment of developmental neurotoxicity was developed under OECD auspices in 1999, 106 although a revision is still under review.

The number of chemicals that can cause neurotoxicity in laboratory studies probably exceeds 1000, which is far more than the estimated 200 that have caused documented human neurotoxicity. However, in the absence of systematic testing, 28 the true extent of the neurotoxic potential of industrial chemicals is unknown. The physiology of brain development 12–14 and experimental evidence14,26,27 suggest that developmental neurotoxicity is likely for all of them, except perhaps for some of the compounds that require metabolic transformation to become neurotoxic, in which immature metabolism may provide some degree of protection. 19,107 The few substances proven to be toxic to human neurodevelopment should therefore be viewed as the tip of a very large iceberg (figure 2).

Large-scale, prospective epidemiological studies, such as birth cohorts from Europe 108 and the National Children’s Study proposed in the USA, will be especially informative about early toxic exposures and neurodevelopmental disorders. 109 Data from these investigations, especially when pooled internationally, will hopefully provide dose-response associations that can guide future disease prevention efforts. This research should move beyond repeated assessments of known neurotoxins to examine chemicals, whose toxicity is just beginning to be recognised. The substances listed in the panel, especially those most prevalent in food, drinking water, and the environment, should provide a useful starting point. Nevertheless, these initiatives could take decades to generate the type of detailed documentation required for chemicals regulation.

The Food Quality Protection Act in the USA requires that pesticide standards be set at values that will protect infants against developmental toxicity. If testing data are not available, a child-protective safety factor should be used in standard settings. However, application of this factor has been uneven, and regulatory authorities need to recognise the vulnerability of prenatal brain development.

Prevention of neurodevelopmental disorders of chemical origin will need new approaches to control chemical exposures. The vulnerability of the human nervous system and its special susceptibility during early development suggest that protection of the developing brain should be a paramount goal of public health protection. The high level of proof needed for chemical control legislation has resulted in a slow pace of interventions to prevent exposures to lead and other recognised hazards. Instead, exposure limits for chemicals should be set at values that recognise the unique sensitivity of pregnant women and young children, and they should aim at protecting brain development. This precautionary approach, which is now beginning to be used in the EU, would mean that early indications of a potential for a serious toxic effect, such as developmental neurotoxicity, should lead to strict regulation, which could later be relaxed, should subsequent documentation show less harm than anticipated. 110 As physicians, we should use prudence when counselling our patients, especially pregnant mothers, about avoidance of exposures to chemicals of unknown and untested neurotoxic potential.

Fluoride References

89 Mullenix PJ, Denbesten PK, Schunior A, Kernan WJ. Neurotoxicity of sodium fluoride in rats. Neurotoxicol Teratol 1995; 17: 169–77.

90 Xiang Q, Liang Y, Chen L, et al. Effect of fluoride in drinking water on children’s intelligence. Fluoride 2003; 36: 84–94.

91 Lu Y, Sun ZR, Wu LN, Wang X, Lu W, Liu SS. Effect of high-fluoride water on intelligence in children. Fluoride 2000; 33: 74–78.

92 Qin LS, Cui SY. The influence of drinking water fluoride on pupils’ IQ as measured by Rui Wen’s standard [in Chinese]. Chinese J Control Epid Dis 1990; 5: 203–04.