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Response inhibition during Differential Reinforcement of Low rates (DRL) schedules may be sensitive to low-level polychlorinated biphenyl, methylmercury, and lead exposure in children.

Article Excerpt
BACKGROUND: Animal studies have shown that exposure to common, low-level environmental contaminants [e.g., polychlorinated biphenyls (PCBs), lead] causes excessive and inappropriate responding on intermittent reinforcement schedules. The Differential Reinforcement of Low Rates task (DRL) has been shown to be especially sensitive to low-level PCB exposure in monkeys.

OBJECTIVES: We investigated the relationships between prenatal PCB and postnatal Pb exposure performance on a DRL schedule in children. We predicted that a) prenatal PCB exposure would reduce interresponse times (IRTs) and reinforcements earned, and b) postnatal Pb exposure would reduce IRTs and reinforcements earned.

METHODS: We tested 167 children on a DRL20 (20 sec) reinforcement schedule, and recorded IRTs and the number of reinforced responses across the session. We measured prenatal PCB exposure (cord blood), methylmercury (MeHg) (maternal hair), and postnatal Pb exposure (venous blood), and > 50 potentially confounding variables.

RESULTS: Results indicated impaired performance in children exposed to PCBs, MeHg, and Pb. Children prenatally exposed to PCBs responded excessively, with significantly lower IRTs and fewer reinforcers earned across the session. In addition, exposure to either MeHg or Pb predicted statistically significant impairments of a similar magnitude to those for PCBs, and the associated impairments of all three contaminants (PCB, MeHg, and Pb) were statistically independent of one another.

CONCLUSIONS: These results, taken with animal literature, argue the high sensitivity of DRL performance to low-level PCB, MeHg, and Pb exposure. Future research should employ behavioral tasks in children, such as DRL, that have been demonstrably sensitive to low-level PCB, MeHg, and Pb exposure in animals.

KEY WORDS: differential reinforcement of low rates, DRL, fixed interval, inhibition, PCBs, polychlorinated biphenyls. Environ Health Perspect 114:1923-1929 (2006). doi:10.1289/ehp.9216 available via http://dx.doi.org/ [Online 18 August 2006]

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Research examining the impact of low-level polychlorinated biphenyl (PCB) exposure on the behavior of children has been performed in a variety of studies over the past several years (Jacobson and Jacobson 1996, 2003; Patandin et al. 1999; Stewart et al. 2005; Walkowiak et al. 2001). In general, the data have supported the hypothesis that low-level PCB exposure predicts small but statistically significant impairments on global tests of cognitive function (Jacobson and Jacobson 1996; Patandin et al. 1999; Schantz et al. 2003; Stewart et al. 2003a; Walkowiak et al. 2001), although an exception has been noted (Gray et al. 2005). Regardless of the merits of the evidence concerning the impact of PCB exposure on global cognitive development in children, one cannot help but be struck by the disconnect between the approaches to studying the neurobehavioral associations with PCBs in humans versus the approaches to studying these same effects in animals. The child cognitive development literature is generally dominated by reliance on standardized, psychometric assessments of global cognitive development, which rely heavily on language for proper performance. In contrast, research with laboratory animals has often involved assessments of specific behavioral domains that require classical experimental approaches. These investigations include the study of PCB-related effects on schedule-controlled behavior (Berger et al. 2001; Lilienthal et al. 1990; Rice 1997, 1999), as well as the assessment of several domains of nonverbal learning, such as attention and associative processing (Widholm et al. 2004), spatial learning (Widholm et al. 2001), and behavioral inhibition (Rice 1997, 1998, 1999).

In several important ways, animal and human research can perform complementary functions to cross-validate the associations seen in the respective literatures. In most cases, however, human research can benefit the most from this relationship: It is far easier to adapt tests used to evaluate neurobehavioral functions from animals to humans than the reverse. Even further, significant PCB findings from carefully controlled, animal experiments usually leave little doubt that PCBs are the causative agent, rather than some unknown confound. Thus, animal results can provide strong evidence about the specific neurobehavioral functions that are impaired by PCB exposure, and direct us toward the specific measures most sensitive in detecting these effects.

Growing evidence in the animal literature demonstrates that behavioral inhibition during reinforcement schedules is quite sensitive to several environmental contaminants, including PCBs (Berger et al. 2001; Lilienthal et al. 1990; Rice 1997, 1998, 1999) and postnatal lead (Cory-Slechta 1990; Cory-Slechta et al. 2002). Nowhere is this more clearly demonstrated than in studies of the performance of animals on delayed reinforcement paradigms. These are schedules where there are delays between the reinforcers and the responses, whether these delays are contingent on the animal's behavior or not.

Studies of performance on Fixed-Interval (FI) and Differential Reinforcement of Low Rates (DRL) schedules provide two examples of these approaches. Both FI and DRL schedules employ fixed intervals of time (delays) that must expire before a given response is reinforced. For example, in an FI20 or a DRL20 schedule, a response will not be reinforced until at least 20 sec have elapsed since the previously reinforced response. The difference between these schedules is that responses before the expiration of the interval during FI schedules are without consequence, whereas making such premature responses on DRL schedules resets the interval clock to the beginning, resulting in delay of reinforcement. Despite these differences, both these schedules have in common the requirement to learn to withhold responses before termination of the delay interval. Such behavioral performance can rightly be characterized as a form of response inhibition (Barkley 1997, 1999).

Interestingly, exposure to both postnatal Pb and postnatal PCBs cause excessive and premature responding on both FI and DRL schedules in animals. Similarly, several well-conducted studies have demonstrated that low-level postnatal Pb exposure causes rats to respond inefficiently and with greater frequency on FI and DRL schedules, as evidenced by an increase in the proportion of short inter-response times (IRTs) on FI schedules (Cory-Slechta et al. 2002) and shorter IRTs and fewer reinforcements on DRL schedules (Rice 1992). In the case of PCB exposure, monkeys exposed to an environmental-relevant mixture of PCBs, at levels found within human populations, showed a much greater response rate during the fixed interval (i.e., shorter IRTs) and, consequently, retarded acquisition of the schedule (Rice 1998). This finding has been replicated with rats (Berger et al. 2001; Carpenter et al. 2002). Rice (1998) also reported a large and statistically robust impairment on DRL schedules in monkeys exposed to low levels of PCBs. These PCB-exposed primates responded excessively and inefficiently, resulting in fewer earned reinforcements. Rice (1998) described the effects of PCBs as an inability to withhold or delay inappropriate responding.

These data provide important clues about the behaviors and assessment tools that would be most sensitive to PCB exposure in humans. Yet it is unfortunate that not a single study has attempted to replicate these findings in children exposed to PCBs or Pb, let alone dissociate such putative effects from confounding contaminants, such as methylmercury (MeHg). This shortcoming is further underscored by the observation that there already exist clues in the literature on humans to suggest that exposed children will exhibit similar response inhibition impairments to those observed in animals. Stewart et al. (2003b) showed that children exposed prenatally to PCBs have demonstrated excessive responding during continuous performance tasks (CPT), which are traditional measures of attention and impulse control. A follow-up study suggested these deficits appear to be caused not by a tendency to initiate large numbers of responses, but rather by an impairment in the ability to inhibit and/or withhold them (Stewart et al. 2005).

Given the wealth of animal data showing PCB- and Pb-related impairments on delayed reinforcement schedules on one hand and the emergent human studies of impulsive behavior on the other (Stewart et al. 2003b, 2005), we examined performance on delayed reinforcement schedules in...