Relationship between lead exposure, cognitive function, and drug addiction: Pilot study and research agenda

ARTICLE IN PRESS Environmental Research 108 (2008) 315–319

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Short Communication

Relationship between lead exposure, cognitive function, and drug addiction: Pilot study and research agenda Diana H. Fishbein a,, Andrew C. Todd b, Erin P. Ricketts c, Richard D. Semba d a

Transdisciplinary Behavioral Science Program, RTI International, 6801 Eastern Avenue, Suite 203, Baltimore, MD 21224, USA Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY, USA Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA d Johns Hopkins Medical Institutions, Baltimore, MD, USA b c

a r t i c l e in fo

abstract

Article history: Received 1 November 2007 Received in revised form 15 July 2008 Accepted 22 July 2008 Available online 27 August 2008

Lead toxicity has been associated with behavioral handicaps, reading disability, antisocial and hyperactive behavior, juvenile delinquency, and impaired cognition. In addition, preclinical studies suggest an association with drug addiction; e.g., animals treated with lead either pre- or postnatally self-administer opiates at a much higher rate than untreated animals. Iron deficiency further increases the risk of lead toxicity through enhanced absorption of lead in the gastrointestinal tract. Female injection drug users have a high prevalence of iron deficiency, although the question remains as to whether this relationship is either a partial function of high lead exposure or heroin use. Specific aims were to preliminarily determine whether female injection heroin users have high tibial lead concentrations, a marker for cumulative lead exposure, compared with normal reference populations, and whether cognitive deficits potentiated the relationship between lead exposure and frequency of heroin use. Tibial lead concentrations were measured via 109Cd-based K-shell X-ray fluorescence. In 26 female injection heroin users, mean (standard deviation (SD)) tibial lead concentration was 14.5 (6.8) mg/(g bone mineral), which was 1.8 times higher than the tibial lead concentration found among age-adjusted normal community-dwelling women. Interaction effects of tibial lead concentration and selected cognitive functions on frequency with which heroin was used were significant. Further research is warranted to determine whether a history of lead exposure is associated with increased proclivity to drug addiction. & 2008 Elsevier Inc. All rights reserved.

Keywords: Injection drug use Heroin Lead Tibia Women

1. Introduction Lead (Pb) exposure and lead toxicity remain a major public health problem in the United States, especially among minority and low-income families residing in older, inner city areas (Brody et al., 1994). Pb toxicity is associated with impaired neurobehavioral development, lower intelligence, and decreased nerve conduction velocity (Centers for Disease Control and Prevention, 1991). Behavioral and developmental problems that may become permanent in children with Pb toxicity include speech and language handicaps, poor attention span, excitability and impulsiveness, and stunted growth. Early exposure to Pb is associated with a seven-fold increase in the rate of high school failure and six-fold increase in reading disability (Needleman et al., 1990). Antisocial behavior and juvenile delinquency have also been linked with Pb toxicity (Needleman et al., 1996, 2002; Dietrich et al., 2001). Pb exposures that were previously thought to be

 Corresponding author. Fax: +1 410 633 8778.

E-mail address: dfi[email protected] (D.H. Fishbein). 0013-9351/$ - see front matter & 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.envres.2008.07.012

without consequence are associated with an increased risk of impaired renal and cardiovascular function and impaired cognition (Navas-Acien et al., 2007; Shih et al., 2007). There is also preclinical evidence that Pb exposure may be related to propensity to drug addiction, in particular to opiates (Rocha et al., 2004). Animals tend to increase the frequency and quantity with which they self-administer opiates after exposure to lead, both prenatally and postnatally. Studies suggest that Pb exposure may reduce sensitivity within the brain’s mesolimbic dopaminergic system, the neural reward circuitry involved in abusable drug effects, thus increasing the dosage and frequency required to achieve desired effects (Rocha et al., 2004; Valles et al., 2003). In humans, however, it remains unknown whether the putative linkage between Pb exposure and drug addiction may also involve factors that co-occur with high prevalence of Pb exposure and that have been more directly associated with risk for drug addiction, such as socio-economic disadvantage (Lansdown et al., 1986; Winneke and Kraemer, 1984) or environmental stress (Cory-Slechta, 1995). Also possibility is that cognitive deficits (potentially due to lead effects and/or drug usage) potentiate this relationship. Bleecker et al. (2007) reported that cognitive reserve

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protected against the effects of lead on cognitive function but not motor function, which provides some indirect support for this possibility. No other studies have been conducted, however, on the interaction effects of Pb and cognitive functioning on any aspect of drug-taking behaviors. Female injection heroin users in inner city Baltimore are at particularly at high risk of Pb toxicity (Kwong et al., 2004) likely due to several coincident conditions, such as economic disadvantage, poor regulation of older buildings in Baltimore, poor medical care, inadequate nutrition, and their drug and alcohol use itself which can exacerbate lead’s effects (Baraldi et al., 1988; Mendola et al., 2002; Nation et al., 2003). Compounding matters, the prevalence of iron deficiency is also extremely high in this population (Semba et al., 2002). Iron deficiency may further increase the risk of Pb toxicity because intestinal absorption of Pb is enhanced in persons with iron deficiency (Kwong et al., 2004). Divalent metal transporter II is upregulated in enterocytes during iron deficiency and is capable of transporting Pb for absorption in the absence of iron (Bannon et al., 2002). Cumulative Pb exposure is indicated by bone (tibial) Pb concentrations, and in vivo K-shell X-ray fluorescence provides a non-invasive approach for measurement of bone Pb (Kosnett et al., 1994). About 95% of the Pb is sequestered in bone in adults, where it has a biological residence time of years-to-decades, depending on the bone type (Chettle, 1995; Gerhardsson et al., 1993; Rabinowitz et al., 1976). We hypothesized that female injection drug users from inner city Baltimore would have high tibial Pb concentrations compared with concentrations found in non-occupationally exposed community populations. Also, we examined relationships among tibial Pb concentrations, selected cognitive functions, and frequency of heroin administration in order to test the hypothesis that the presence of both higher levels of tibial lead concentrations and poorer cognitive performance would be associated with increased frequency of heroin injection. The latter hypothesis was based on the preclinical work, mentioned above, suggesting that lead exposure reduces sensitivity of neural reward structures implicated in higher rates of opiate self-administration. To address these hypotheses, we measured tibial Pb concentrations and assessed cognitive function, drug-use histories and background factors in female injection heroin users.

2. Materials and methods 2.1. Participants The study subjects consisted of 26 female injection heroin users in Baltimore, Maryland who had participated in a clinical trial of micronutrients and were asked to return and participate in an ancillary study which involved a measurement of tibial Pb concentration. Women were eligible for the original clinical trial if they satisfied each of the following conditions/criteria (1) 18 years of age or older, (2) resident in Baltimore at the time of the ancillary study, (3) history of injectiondrug use in the last 10 years, (4) hepatitis C positive, (5) no history of betathalassemia, sickle cell anemia, or hemochromatosis, (6) no history of renal failure or end-stage liver disease, (7) no history of interferon therapy of duration in excess of 3 months, (8) premenopausal, (9) Karnofsky status (indicative of functional impairment) 480%, and (10) not pregnant as determined by a urine screen. Women were enrolled after written, informed consent and the data were collected in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of the Johns Hopkins School of Medicine. Full cognitive and background data were available for 18 of these participants; thus, analyses including cognitive measures were therefore restricted to this subsample.

(DATOS: Hubbard et al., 2003) and additional study-specific questions. Drugs of abuse considered in this assessment included tobacco, alcohol, marijuana, cocaine, and heroin with respect to the following attributes: frequency of administration during regular periods of use (0 ¼ less than 1 day a month; 1 ¼ 1–3 days a month; 2 ¼ 1–2 days a week; 3 ¼ 3–4 days a week; 4 ¼ 5–6 days a week; 5 ¼ every day; 6 ¼ a few times a day), age of onset, date drug was last used regularly, and date of more recent use. Demographics were assessed by the inclusion of items regarding employment, marital status, living arrangements, education, mental and physical health status, legal system involvement, family history of mental illness, drug addiction, and criminality, victimization, and phase of the menstrual cycle during cognitive testing. 2.2.2. Cognitive measures The task battery for this study was selected on the basis of two sets of pertinent literature: (1) studies showing the relationship between Pb exposure and neuropsychological deficits and (2) studies showing an association between drug addiction and neuropsychological deficits. The selected short battery of tests is indicative of those functions which have a high likelihood of being affected by Pb and greater vulnerability to addiction: executive decision making, cognitive flexibility, and impulsivity. The Cambridge Decision Making Task (CDMT) was developed to dissect cognitive abilities believed to affect risky decision making as defined by selecting an unlikely large reward associated with an equally large penalty rather than a likely, small reward/penalty, a form of affective disinhibition (Rogers et al., 1999a, b). The CDMT has been consistently shown to activate the orbitofrontal cortex in normal controls (Rogers et al., 1999a) and to generate lower levels of anterior cingulate activity in drug addicts (Fishbein et al., 2005). This task and the functions it taps are described in Fishbein et al. (2005). Performance measures generated include percentage of choosing the least likely outcome (i.e., percent total high risk choices), capturing the conflict inherent in risk-taking situations. The Logan Stop-Change Task (SCT) measures an aspect of inhibition that involves the ability to shift responses in light of new information (see Logan and Burkell, 1986), a function which has been shown to activate the right hemispheric anterior cingulate cortex, supplementary motor area, and inferior prefrontal and parietal cortices, which modulate error monitoring, interference control, and task management (Rubia et al., 2001). The task consists of two parts: (1) the baseline to assess the participants’ reaction time when pressing a button corresponding to a circle or star on the screen and (2) the main (active) task to assess the participants’ ability to inhibit a prepotent response and initiate a new response (i.e., different button press) when a tone intermittently occurs after the circle or star is presented. Tones were presented in 25% of the trials at four different intervals following the imperative stimulus (i.e., the star or circle): 100, 250, 350, and 500 ms. Inhibition of a prepotent response was easier with the shorter delays (e.g., 100 ms) than the longer delays (e.g., 500 ms). Measures from this task include percentage correct for all trials combined and each trial type separately. The Stroop Color Word Interference Task (Bench et al., 1993; Pardo et al., 1990) uses previously learned information so that three attributes of executive frontal lobe function reflective of cognitive flexibility can be assessed: (1) complexity; (2) a ‘‘nonroutine’’ nature; and (3) the novel use of old information. Patients with frontal lobe damage are typically influenced by stereotypical thinking, which would interfere with the ability to produce the atypical responses required on the Stroop (Luria, 1980; Mesulam, 1986), and often experience difficulty with mental flexibility as measured by the Stroop (Stuss and Benson, 1986). Imaging studies suggest that the anterior cingulate is involved in Stroop performance (Pardo et al., 1990; Bench et al., 1993). Basic measures generated for this task are the Word Score, Color Score, and Predicted Color-Word Score, and Interference Score. The central measure ‘‘interference’’ derives from these scores and is calculated by multiplying the first two conditions and dividing that product by the sum of those conditions to produce a ‘‘CW0 ’’ score (WxC/W+C ¼ CW0 ). The sum of third condition is then subtracted by the CW’ score (CWCW0 ¼ interference). 2.2.3. Cumulative lead exposure Tibial Pb concentration was measured non-invasively and in vivo via a 30-min (clock time) measurement of the mid-tibia shaft of the left leg (for all but two of the subjects) wherein the K-shell X-rays of lead were fluoresced with the g-rays emitted by 109Cd (Todd and McNeill, 1993; Todd et al., 2002). The XRF method provides an estimate of the measurement error in the estimate of tibia lead concentration for each subject. The measurement error is derived from peak size uncertainties returned by the non-linear, least-squares peak extraction method, in combination with the uncertainty arising from calibration (Todd, 2000; Todd and Chettle, 2003). Tibial Pb concentrations were expressed in units of mg Pb per gram of bone mineral (hereafter mg/g).

2.2. Measurement instruments 2.3. Statistical techniques 2.2.1. Background and drug-use history Participants were administered a questionnaire to assess demographic characteristics and drug-use histories. The instrument, coined the ‘‘DATASI,’’ was created by combining relevant items from the Addiction Severity Inventory (ASI: McLellan et al., 1992), the Drug Abuse Treatment Outcome Study

Initially, a mean and standard deviation (SD////) for tibial Pb concentrations in this sample was computed for comparisons with non-occupationally exposed subjects published in the literature (Erkkila¨ et al., 1992; Gamblin et al., 1994; Roy et al., 1997; Somervaille et al., 1988). Also, univariate distributions were examined

ARTICLE IN PRESS D.H. Fishbein et al. / Environmental Research 108 (2008) 315–319 for each parameter to qualitatively assess the normality of the data; to assess their suitability for regression analysis; and to identify leverage points and data of potentially undue influence. The data were deemed sufficiently normal in their untransformed state for a small scale regression analysis. Subsequently, initial regression analyses were conducted to determine whether tibia lead (independent variable) and cognitive functions (dependent variables) were associated. Regression analyses were also used to evaluate the association between cognitive function and frequency of heroin addiction. A simple correlation analysis was conducted to assess the relationship between tibial lead concentration and frequency of heroin use. In order to explore the possibility that tibia lead concentrations would interact with level of cognitive functioning to ‘‘predict’’ frequency of heroin use, linear regression models were tested. Frequency of heroin use, the dependent variable, was defined by how often heroin was injected during the period of active use (see categorization scheme above). For each of the three independent variables, interaction terms were computed for Pb by impulsivity (percent correct on the SCT), Pb by executive decision-making (percentage of risky [disadvantageous] choices on the CDMT), and Pb by cognitive flexibility (interference score on the Stroop). Age and education were entered into each model as covariates. Given the small sample size of this pilot study, statistically significant findings are reported to help to direct future investigations.

3. Results The demographic characteristics and cognitive scores of all study subjects (n ¼ 26) are shown in Table 1. In this sample of female injection heroin users, the mean (SD) tibial Pb concentration was 14.5 (6.8) mg/g. The average age-adjusted tibial Pb concentration in non-occupationally exposed women was calculated to be 8 mg/g (1.15) from associations between tibia lead and age for non-occupationally exposed women in the literature (Erkkila¨ et al., 1992; Gamblin et al., 1994; Roy et al., 1997; Somervaille et al., 1988). For all cognitive measures, the scores reflect some degree of deficit relative to what would be expected in a healthy population; 48% risky choices is higher (e.g., 23.3% in Rogers et al., 1999a, b), 29% correct on all tone trials is substantially lower (e.g., 73% in Fishbein et al., 2007), and 6.52 for the Stroop Interference raw score indicates greater inflexibility (e.g., 12.9 in Fishbein et al., 2007) than normal controls (Table 2). For the subset with cognitive data, tibial Pb concentrations were significantly and positively related to risky decision making (t ¼ 2.32; po.05). Primary impulsivity and cognitive flexibility scores were not significantly associated with tibial Pb concentrations. Frequency of heroin use was not, however, directly related to tibial Pb concentrations or to cognitive measures. Tests of the primary hypotheses found that interactions between cognitive inflexibility and Pb (t ¼ 3.28; p ¼ .007) and risky decision making and tibial Pb (t ¼ 3.26; p ¼ .05) were Table 1 Characteristics of female injection-drug users (n ¼ 26) in Baltimore, Maryland Characteristic

% or mean (SD)

Age (years)

42.5 (5.1)

Race (%) White, non-hispanic Black, non-hispanic Other Level of education (years) Frequency of heroin injection Hemoglobin (g/L) Ferritin (ng/mL) Tibial lead (mg/g) Tibial lead (% of normal)a Stroop: cognitive flexibility raw score CDMT: risky decision making SCT: impulsivity

9.7 61.3 3.2 11.17 (1.25) 3.39 (3.25) 12.85 (1.66) 67.31 (68.34) 14.5 (6.8) 8.0 (1.15) 6.52 (4.63) .48 (.18) .29 (.22)

a Percent of mean of estimates of non-occupationally exposed tibia lead for this age and gender.

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Table 2 Interaction effects of tibial Pb and cognitive functioning on frequency of heroin use Model

Standardized beta coefficients

t

p value

Age at enrollment Education Tibial Pb by cognitive flexibility Tibial Pb by risky decisions Tibial Pb by impulsivity

.04 .49 .80 .75 .06

.15 2.10 3.28 3.26 .32

.88 .06 .007 .007 .75

Linear regression model with age and education as covariates (n ¼ 18). Model R2 ¼ .61, F change ¼ 3.80, sig. F change ¼ .02.

significantly related to frequency of heroin use. Also, the interaction between cognitive inflexibility and tibial Pb was associated with age of onset of heroin use; specifically, the younger the age of onset, the less cognitive flexibility these women exhibited in interaction with cumulative Pb exposure as measured by tibial lead concentration (t ¼ 2.46; po.05). The overall model was significant (R2 ¼ .61, F Change ¼ 3.80, p ¼ .02). Additional regression models were tested to determine whether these relationships applied as well to the frequency of tobacco, alcohol, marijuana, and cocaine use, but none was significant. The frequency of use for each drug also did not influence the primary relationship between the interaction terms and frequency of heroin use (data are not shown).

4. Discussion To date, no human studies have been conducted to ascertain whether Pb exposure is related to propensity for drug addiction, despite the preclinical literature showing that animals will selfadminister abusable drugs more readily after early Pb exposure (e.g., Nation et al., 1996, 2003; Miller et al., 2000; Rocha et al., 2004), and despite the common concurrence of these two conditions across many communities (Ensminger et al., 1997). Nor is our study the first to do so since it was limited to injection drug using females in Baltimore City and did not include a comparison group. Although a control group of non-heroin/nonsubstance abusing is preferable, comparison groups for bone lead measurements is not as straightforward as in other epidemiological situations, inasmuch as, (1) most people are exposed to lead (particularly in cities like Baltimore) and thus there are, in a sense, no appropriate ‘‘controls’’, (2) the ‘‘natural’’ concentration of lead in bone is orders of magnitude less than the levels observed in our study, and the same number of orders of magnitude less than would have been observed in measurements of non-heroin/nonsubstance-abusing controls from Baltimore or elsewhere in the US, and (3) the bone lead concentrations were compared with the concentrations that would have been expected for a person of the same age and gender as the study subjects, calculated from published studies of non-occupationally exposed persons and are, therefore, ‘‘normalized’’ to the extent that the term applies to bone lead concentrations. In spite of its shortcomings, this preliminary investigation was intended to be a first step in the exploration of whether (1) tibial Pb concentrations were elevated in this sample relative to nonoccupationally exposed subjects, (2) tibial Pb was directly related to frequency of heroin use, and (3) the interaction between tibial Pb and cognitive function was related to frequency of heroin use. These initial results are suggestive of significantly greater exposures to Pb among female heroin addicts in Baltimore City than in the general community given values for a normal reference group. Furthermore, there is some support for the possibility that tibial lead, in particular and, by extension, bone

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lead in general relates to frequency of heroin use, but only in the presence of a decrement in cognitive function. Importantly and unexpectedly, frequency of heroin use was not directly associated with measures of executive cognitive function in this small sample. Also unexpected were the lack of relationships with frequency of other drug use. Noteworthy is that this population may differ somewhat in that, while most addicts are polydrug users, Baltimore is characterized by its prevalence specifically of heroin addiction. Also, the recruitment criteria (i.e., injection drug use) must be considered. Associations generally explored in this study may be more complex than previously considered, if our small sample size is not responsible for the absence of expected relationships. In either event, these preliminary findings should not be overinterpreted given the substantial limitations of this pilot study’s design; the purpose of this initial exploration was to stimulate further clinical work to more rigorously test these hypotheses.

4.1. Future research agenda The results from this pilot study provide some fuel for moving forward with a more substantial and concerted research agenda to address several unanswered questions. First, a descriptive examination of a large urban-based community sample such as Baltimore is warranted to determine whether there is a greater incidence of drug addiction (considering both past and present addiction status) among those with higher cumulative Pb exposures than those with lower cumulative Pb exposures. If support is found for the simple association between drug addiction and Pb exposure, the role of neighborhood-level conditions must be defined given that the prevalence of Pb exposure in the urban environment coincides with a high level of socio-economic disadvantage and adversity which is well established as a significant risk factor in drug addiction (Ensminger et al., 1997). Animal studies of chronic low-level Pb exposure and stress have yielded significant interaction effects on drug-taking behaviors (Valles et al., 2003). Interestingly, Cory-Slechta (1995) found evidence for potentiation of Pb effects by stress on cognitive deficits with potential to trigger or exacerbate behavioral dysfunction. Thus, it appears that psychosocial stress may moderate the effects of Pb exposures on propensity for dysregulated behaviors. Another potential area of inquiry would be the extent to which decrements in cognitive function from Pb exposure mediate the relationship between Pb exposure and drug addiction and whether the main effects of Pb concentrations and addiction are stronger than main effects (which we consider to be still a viable possibility despite not being directly supported by this small pilot). Cognitive deficits, particularly in executive functions, constitute significant liability factors in risk for, and development of, addiction (Aytaclar et al., 1999; Blume et al., 1999; Giancola et al., 1996, 1998; Moss et al., 1997; Tarter et al., 1995; Weinberg, 1997), irrespective of the origins of such deficits. Hence, it seems reasonable to hypothesize that cognitive functional deficits may contribute to an explanation of the relationship between lead exposure and addiction. There are several other possible explanations, however, that would also need to be addressed for a better understanding of this relationship: (1) greater cumulative lead exposure may be associated with greater cognitive impairment and, in turn, propensity for addiction; (2) greater cumulative lead exposure may only be associated with level of addiction given mediation by cognitive function; or (3) some individuals may be more susceptible to Pb’s effects on cognitive function, and thus show moderate levels of Pb exposure but greater cognitive deficits and levels of addiction. A variety of factors may influence

possibility #3, including iron deficiency (which was unrelated to cognitive function in the present sample) or other nutritional deficit, severe stress, other drug or alcohol abuse, prenatal drug exposures, or other environmental and psychosocial sources. On the other hand, a more direct effect of Pb on neurobiological systems that influence reward value of drugs may increase susceptibility to addiction, irrespective of cognitive function, as has been suggested by preclinical studies (e.g., Nation et al., 1996, 2003; Miller et al., 2000; Rocha et al., 2004). Evidence for the mediating role of reward systems in this relationship would suggest that Pb exposure directly enhances drug-seeking behavior. Increasingly, the research literature suggests that developmental Pb exposure can produce long-lasting changes in drug responsiveness, even after exposure to the toxicant has been discontinued. Although the mechanisms by which Pb may exert its effects on propensity to drug addiction have yet to be elucidated, evidence implicating lead-induced change in dopaminergic systems, integral to the rewarding effects of abusable drugs, is compelling (Cory-Slechta, 1995; Tavakoli-Nezhad and Pitts, 2005). This possibility does not, however, preclude the role of cognition given that dopaminergic systems are also involved the development and function of executive cognitive functions. In summary, although the present study constituted only an initial exploration of the putative relationship between cumulative Pb exposures and drug addiction, the extant preclinical and human literature and the preliminary findings of this study suggest that further research is warranted. Such research may result in public health and prevention programs that produce significant improvements in integrity of long-term cognitive and behavioral outcomes.

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