ADHD, lead exposure and prevention: how much lead or how much evidence is needed?

Despite its well-documented and much touted high heritability, the environmental causes of attention-deficit/hyperactivity disorder (ADHD) are a growing concern on the US research agenda [1,2]. One reason is resurgent political, consumer and medical concern with the potential harmful nature of children’s environments on their health across a range of modern child epidemics, including obesity, asthma, cancer, and learning and behavioral disorders [3]. Another reason is growing scientific recognition of the importance of gene–environment interplay in neural development, including environmental modulation of gene expression that can play a role in the development of psychopathology even for heritable disorders [4]. Under this perspective, genes can be used to gauge the true strength of environmental influences more accurately, by showing how strong these effects are in the portion of the population that is genetically liable to the disorder. A third influence is the recognition that disorders like ADHD are sufficiently costly to society and difficult to treat once they bloom that investments in prevention are well justified if only an effective and ethically acceptable preventive strategy can be identified.

This confluence of concerns has begun to move identification of environmental effects up the research agenda for ADHD. Identifying such prevention opportunities relies as much on targeting the relevant environments as the relevant genes. It opens up important areas of inquiry, such as toxicogenomics, to examine how toxins affect the genome to create disease.

With regard to prevention strategies, such environmental targets fall into at least two major classes. In the first class are those injurious experiences under the control of individual parents, often already known to be harmful. Examples in this class are prenatal cigarette and alcohol exposure (in the case of ADHD and related conditions [5]), excessive exposure to violent television programming (in the case of aggression [6]), physical or sexual abuse (in the case of a range of outcomes), and inadequate maternal and child nutrition. Despite being well-recognized scientifically, these readily prevented exposures remain stubbornly difficult to eradicate and are a continued focus of public health efforts. These exposures may fall under the rubric of shared or non-shared environment in the usual parcing of variance in twin studies, but are probably best viewed as the product of genotype–environment interplay. Prevention entails identification and outreach to risk-behaving individual parents or groups of parents. Research focuses on the most effective strategies for doing so.

In the second class are those injurious agents that are widely distributed in children’s environment and are typically beyond the control of individual parents to prevent. Examples include exposure to the thousands of industrial toxins, pesticides, organic pollutants, heavy metals, ozone and air pollution and other injurious agents that permeate modern societies and the world [7]. Many of these potentially neurotoxic exposures are poorly understood and too often treated by society as the ‘necessary cost of doing business’ in a modern economy. However, the actual cost, thus written off, may be higher than initially believed if in some instances it includes such costly disorders as ADHD. Key targets that appear to be relevant to ADHD risk include persistent organic pollutants (such as polychlorinated biphenyls and dioxins) and lead [8]. These agents appear to attack the same neural systems already known to be involved in ADHD, and may interact with the genes already suspected in ADHD, in addition to other genes not yet identified.

These exposures, to the extent they are universal in the population (often the case if one looks at low level, background exposures worldwide), are highly likely to be shared environment effects in the population. Such effects are the type most likely to inflate heritability estimates if they interact with genotype to produce disease [8,9].

Aside from the astonishing lack of knowledge regarding their effects on neural development that accompanies dissemination of these products into children’s early developmental environment [7], there is another disturbing characteristic that neurotoxic compounds too often seem to share: the more research is done, the lower the threshold of harm.

This finally brings me to the topic in the title of this editorial: lead exposure. Lead stands almost alone with regard to how well recognized and how dangerous it is as a pollutant that children can ingest after birth. At the same time, it is a model toxicant with regard to its neural effects: if it can be fully understood, the effects of other pathways to ADHD may become more tractable.

Once widely utilized in paints, automotive fuel and other applications, the dangers of lead were so apparent that it began to be heavily regulated in the 1970s in the USA. In 1991, in response to evidence of its effects on cognitive development, the CDC further lowered the definition of elevated blood concentration of lead from 25 µg/dl to 10 µg/dl (approximately ten parts per 100,000). In addition to effects on IQ and on poor cardiac health, the association of blood lead above 10 µg/dl with hyperactivity and attention deficits was clear in the literature of the past 20 years: it was replicated in numerous prospective and cross-sectional studies, survived a wide range of conceivable covariates and proved causal in animal models [10–15]. This aspect of the ADHD story is often overlooked today because these higher lead exposures are now relatively rare in the USA.

However, the story of the remaining common low-level lead effects is still not fully told. More recently, a series of studies have documented that early life exposure to lead, peaking at blood levels far lower than the elevated exposure level (down to 2 µg/dl), is associated with meaningful reduction in IQ [16]. Furthermore, even in the range 0–5 µg/dl, blood lead has now been related to ADHD in both population surveys [17] and in a recent case–control design with levels ranging 1–3 µg/dl [18]. The latter study also found that lead was related to weakened cognitive control, a mechanism often associated with risk for ADHD via breakdowns in frontal–striatal neural circuits. Longitudinal work, replications and gene–lead studies will be forthcoming and informative. Yet it seems likely that lead’s effects will prove not to be uniform, but rather to affect some children more than others based on genetic or other liability (just as is the case with smoking and lung cancer or with infectious agents and infectious disease).

It may seem puzzling that a risk factor has been reduced in the population, yet has not led to a major reduction in the incidence of the illness. However, many additional neural toxicants have in the meantime been added to the environment, that dwarf any benefit of having reduced lead exposure in the population [7]; moreover, if the lead effects on ADHD occur at low levels and are nonlinear, then the risk remains much as it was before. The disturbing trend of this work is the conclusion that there is no ‘safe’ level of lead exposure for young children. How many chemicals and other nanoproducts will yield the same conclusion over the next few decades, and how many children will be injured in the meantime? This is the stark situation that prevention policymakers face.

Scientifically, the field has a responsibility to understand the interplay of such widespread environmental risks with genotype in explaining the neural mechanisms of ADHD and related disorders. However, at the policy level, the European Union and other nations are moving in the direction of a prevention-based policy for regulating chemicals in children’s environment [101], amid much controversy as to the economic inconvenience of such regulation. This controversy is because costs heretofore borne by children, schools, hospitals and taxpayers would now be born by manufacturers and their customers. Naturally, the manufacturers object.

The regulatory framework still used in the USA is ‘no proven harm’. This is a relatively weak standard of proof to allow release of a product because it falls prey to the logical rejoinder that ‘absence of proof is not proof of absence.’ The new framework, sometimes called a ‘precautionary framework’, adopts the higher standard of ‘proven safe’. Continued scientific efforts to clarify the extent of gene–environmental influences on ADHD can inform such policies. However, in the case of most toxicants, it is something of a waste of scientific and public health resources to chase down causes of psychiatric and physical illness that could be avoided simply by more sensible scrutiny of the optional risks introduced into children’s lives in the first place.

Environmental toxicants are surely not the only important experiential influences on ADHD, but they may play a larger role than previously believed, with lead being just one example that is probably repeated in many other instances, likely including polychlorinated biphenyls and other agents. The mechanisms and effect sizes of such triggers and their varying genetic liabilities could take decades to unravel. In the meantime, it seems prudent to move in a precautionary direction with prevention policy with all chemical and nanotechnologies that place costly risks and burdens on children’s health. Doing so would free up scientific resources to clarify the many remaining contributors to liability to such major disabilities as ADHD, and to designing better treatments for cases that cannot be prevented.

Financial & competing interests disclosure

Work on this paper was supported by the MSU Office of Vice President for Research HBRI funding, R01-MH70004 and 2R01MH059105. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.