Kosnett et al. 2007 Measurement of lead dose Hu et al. 2007 in vivo in vivo Published reviews of relevance to this review Balbus-Kornfeld et al. 1995 Goodman et al. 2002 Meyer-Baron and Seeber 2000 Balbus-Kornfeld et al. (1995) Goodman et al. (2002) Meyer-Baron and Seeber (2000) Goodman et al. 2001 Schwartz et al. 2002 Seeber and Meyer-Baron 2003 Seeber et al. 2002 Goodman et al. (2002) Seeber and Meyer-Baron 2003 Goodman et al. (2002) Goodman et al. 2002 Meyer-Baron and Seeber (2000) Goodman et al. (2002) Meyer-Baron and Seeber 2000 Methods Methodologic considerations for relations of lead dose and cognitive function Hu et al. 2007 Agency for Toxic Substances and Disease Registry 1999 Annest et al. 1983 Pirkle et al. 1998 Hoppin et al. 1995 Identification of studies National Library of Medicine 2006 American Psychological Association 2006 a b c d e Data abstraction a b c d e f g Results Overview of evidence a b c Table 1 Table 2 Studies of adults without occupational lead exposure Tables 1 2 Stokes et al. 1998 Payton et al. 1998 n n n Weisskopf et al. 2007 ) Weisskopf et al. 2007 Weisskopf et al. (2004) Folstein et al. 1975 Payton et al. 1998 Wright et al. 2003 Shih et al. 2006 Stokes et al. (1998) Hoppin et al. 2000 Studies of occupationally exposed workers Barth et al. 2002 Bleecker et al. 1997 Lucchini et al. 2000 Bleecker et al. 2005 Chia et al. 1997 Lindgren et al. 1996 n Schwartz et al. 2001 n Osterberg et al. 1997 Hanninen et al. 1998 Bleecker et al. (1997) Schwartz et al. (2001) Schwartz et al. 2005 a b c d Stewart et al. 1999 Schwartz et al. 2000 Links et al. 2001 Lead exposure and psychiatric symptoms McNair et al. 1971 Baker et al. 1983 Maizlish et al. (1995) Lindgren et al. (1996) Radloff 1977 Schwartz et al. 2001 Rhodes et al. 2003 Derogatis and Melisaratos 1983 p Arnett et al. 1999 Naismith et al. 2003 Weingartner et al. 1981 Wilson et al. 2002 a b c d Jorm (2000) Lead–gene interactions APOE) 4 Stewart et al. 2002 APOE 4 APOE 4 APOE 4 Mayeux et al. 1995 Discussion Summary of evidence for a causal relationship Balbus-Kornfeld et al. 1995 Consistency of associations n Martin et al. 2006 Shih et al. 2006 Weiss and Bellinger 2006 Strength of association Schwartz et al. 2001 Shih et al. 2006 Weisskopf et al. 2004 Weisskopf et al. 2007 Specificity Ferguson et al. 2000 Ramesh et al. 2001 Temporal relationship Associations between lead biomarkers and cognitive outcomes 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 condition 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) Wright et al. 2003 Shih et al. 2006 Biologic plausibility and experimental data Zawia et al. 2000 Widzowski and Cory-Slechta 1994 Finkelstein et al. 1998 Cory-Slechta 1995 Eichenbaum 2001 Salthouse 1996a 1996b Dufouil et al. 2003 Schafer et al. 2005a Hogervorst et al. 2002 McCaddon et al. 2003 Selley 2003 McCaddon and Kelly 1992 Parnetti et al. 1997 Guallar et al. 2006 Schafer et al. 2005b Martin et al. 2006 Nash et al. 2003 Glenn et al. 2003 2006 Birkenhager and Staessen 2006 Hayden et al. 2006 Skoog and Gustafson 2006 APOE Stewart et al. 2002 APOE 4 Corder et al. 1993 Meyer et al. 1998 Saunders et al. 1993 Moffat et al. 2000 Zubenko et al. 1994 APOE 4 Meyer et al. 1998 APOE 4 Poirier and Sevigny 1998 APOE 4 Miyata and Smith 1996 Teter et al. 1999 Yankner 1996 APOE APOE 4 Stewart et al. 2006 Public health implications The removal of lead from gasoline, paint, and most other commercial products has succeeded in dramatically 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 proportion of cognitive aging; future research will be able to determine whether the chronic effects of cumulative lead dose alter the trajectory of normal cognitive aging. Research efforts should be directed to development of preventive interventions for both lead-associated 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. Petersen et al. 1999