Shih et al. surprising that lead’s toxicity is not speciﬁc to the brain and we do not believe this lack of target organ specificity diminishes the infer- ence for a causal relationship between lead and cognitive dysfunction. Temporal relationship. Associations between lead biomarkers and cognitive out- comes have been demonstrated in both cross- sectional and longitudinal studies. In several of the longitudinal studies, change in cognitive function was explicitly modeled in relation to preceding lead dose or in relation to change in lead dose. In either case, the temporality con- dition is met. In addition, as bone lead is a measure that ascertains prior dose, even in cross-sectional analyses, analysis of bone lead with cognitive test scores evaluates lead dose that preceded current cognitive performance; thus, while cognitive assessment is cross- sectional, dose assessment is retrospective and cumulative. This again would minimize concerns about incorrect temporal relations. Biological gradient (dose–effect relations). Nearly all reviewed studies found a dose–effect relation for blood lead, bone lead, or both. Existing studies do not allow determination of a threshold dose for either blood lead or bone lead or the shape of the dose–effect relationship at low dose levels. Associations have been observed in populations with mean blood lead levels as low as 4.5 µg/dL (Wright et al. 2003) and mean tibia lead levels as low as 18.7 µg/g (Shih et al. 2006). Biologic plausibility and experimental data. Lead adversely affects the brain in a vari- ety of ways. Lead is thought to increase oxida- tive stress, induce neural apoptosis, inﬂuence neurotransmitter storage and release, and damage mitochondria. The ability of lead to substitute for calcium allows it to affect cal- cium-mediated processes and pass through the blood–brain barrier. It may also interfere with zinc-dependent transcription factors, altering the regulation of genetic transcription (Zawia et al. 2000). Animal studies indicate that the accumulation of lead in the brain is generally uniform (Widzowski and Cory- Slechta 1994), although the hippocampus and limbic system, prefrontal cerebral cortex, and cerebellum are clearly principal sites of the effects of lead (Finkelstein et al. 1998). Low lead levels in rats produce structural changes in the hippocampus (Cory-Slechta 1995), a brain region critical for learning and memory (Eichenbaum 2001), which is consis- tent with the ﬁnding of learning and memory deﬁcits in lead-exposed individuals. Blood lead level is a measure of current biologically active lead burden and is there- fore a better marker of the acute effects of recent lead dose. These are likely to be effects on neurotransmission and calcium enzyme- dependent processes such as synaptic plastic- ity. This could lead to circulating blood lead 490 impairing, for example, information storage and retrieval mechanisms or processing speed, which have been suggested to impair perfor- mance on cognitive tests (Salthouse 1996a, 1996b). Lead levels in bone are a measure of cumulative dose over decades as well as a source of lead in the body that is available for mobilization into blood, especially during periods of increased bone turnover (e.g., preg- nancy, puberty). Although lead stored in bone is not directly harmful to the brain, the cumulative effects of chronic lead exposure are likely to be related to oxidative stress and neuronal death and could impair cognitive function, for example, by reducing the capac- ity of speciﬁc regions to process information, or by impairing diffuse ascending projection systems such as the midbrain cholinergic and dopaminergic cells. Lead may also inﬂuence cognitive function indirectly through its effects on blood pres- sure, hypertension, or homocysteine levels. Increased homocysteine levels, a well-known risk factor for cardiovascular disease, have also been associated with risk for poorer cognitive functioning (Dufouil et al. 2003; Schafer et al. 2005a) and risk for dementia (Hogervorst et al. 2002; McCaddon et al. 2003; Selley 2003). Homocysteine is neurotoxic to the cen- tral nervous system by inﬂuencing neurotrans- mitter synthesis, and causing excitotoxicity and cell death (McCaddon and Kelly 1992; Parnetti et al. 1997). Blood lead levels were associated with homocysteine levels as well, although the direction of causality has yet to be determined (Guallar et al. 2006; Schafer et al. 2005b). Both blood and bone lead levels have been linked with blood pressure and hyperten- sion in community-based samples of older adults (Martin et al. 2006; Nash et al. 2003) and occupationally exposed populations (Glenn et al. 2003, 2006). Hypertension has also been identiﬁed as a potential risk factor for dementia (Birkenhager and Staessen 2006; Hayden et al. 2006; Skoog and Gustafson 2006). Thus, lead may indirectly play a role in cognitive declines by way of poor vascular health. We believe the effect modification by APOE genotype offers strong biologic plausi- bility to the inference that lead causes cognitive dysfunction (Stewart et al. 2002). The APOE ε4 allele is a risk factor for late-onset Alzheimier disease (Corder et al. 1993; Meyer et al. 1998; Saunders et al. 1993), hippocampal atrophy (Moffat et al. 2000), and senile plaques (Zubenko et al. 1994). It appears that the APOE ε4 allele lowers the age of onset of the disease and accelerates age-related cognitive decline (Meyer et al. 1998). Mechanistically, APOE ε4 is involved in the recovery response of injured nerve tissue (Poirier and Sevigny 1998), with the APOE ε4 allele having reduced ability to promote growth and reduced antioxi- dant properties (Miyata and Smith 1996; Teter et al. 1999; Yankner 1996). The interaction of APOE genotype with tibia lead level may be related to an impaired ability to counteract injury from lead exposure among APOE ε4 carriers. Another recent study also offers biologic plausibility. In the former organolead workers, tibia lead level was associated with the preva- lence and severity of white matter lesions on brain MRI, using the Cardiovascular Health Study white matter grading system (Stewart et al. 2006). Tibia lead level was also associ- ated with smaller volumes on several regions of interest ranging from large (e.g., total brain volume, lobar gray and white matter volumes) to small (e.g., cingulate gyrus, insula, corpus callosum). As volume can decline because of changes in cell number, synaptic number or density, or other changes in cellular architec- ture, these findings reinforce evidence that lead may cause a persistent change in the brain that is associated with progressive declines in cognitive function. Public health implications. The removal of lead from gasoline, paint, and most other commercial products has succeeded in dra- matically reducing environmental sources of lead exposure, and this has been reﬂected by the parallel declines in mean blood lead levels in Americans over the same time frame. However, lead has accumulated in the bones of older individuals, and especially those of lead workers exposed at the continued higher levels encountered in lead-using workplaces. Thus, past use of lead will continue to cause adverse health effects even when current exposures to lead are much lower than in the past. Lead in bone is not directly harmful to the central nervous system, and most of the structural and neurochemical damage is likely to have occurred decades ago. Nevertheless, lead in bone might serve as a source from which lead can be mobilized into blood, and potentially cross the blood–brain barrier. The chronic effects of lead may account for a pro- portion of cognitive aging; future research will be able to determine whether the chronic effects of cumulative lead dose alter the trajec- tory of normal cognitive aging. Research efforts should be directed to development of preventive interventions for both lead-associ- ated cognitive decline with aging from past exposures, as well as the mobilization of current bone lead stores into the circulatory system leading to new health effects. Cognitive aging occurs in conjunction with the normal biological aging process. It remains to be determined whether lead affects cognitive aging in adults by permanently reducing brain circuitry capacity thereby low- ering baseline cognitive functioning, or by inducing steeper declines in cognitive func- tioning, leading to abnormal cognitive aging. It may be that lead inﬂuences cognitive health VOLUME 115 | NUMBER 3 | March 2007 • Environmental Health Perspectives