In the last decade advances in the analytic methods for quantification of polychlorinated biphenyls (PCBs) have resulted in widespread availability of congener-specific analysis procedures, and large amounts of data on PCB congener profiles in soil, air, water, sediments, foodstuffs, and human tissues have become available. These data have revealed that the PCB residues in environmental media and human tissues may not closely resemble any of the commercial PCB mixtures, depending on source of exposure, bioaccumulation through the food chain, and weathering of PCBs in the environment. At the same time, toxicological research has led to a growing awareness that different classes of PCB congeners have different profiles of toxicity. These advances in analytic techniques and toxicological knowledge are beginning to influence the risk assessment process. As the data from ongoing PCB studies assessing the mediators of neurobehavioral outcomes in children are published, the weight of evidence for PCB effects on neurodevelopment is growing. Studies in Taiwan, Michigan (USA), New York (USA), Holland, Germany, and the Faroe Islands have all reported negative associations between prenatal PCB exposure and measures of cognitive functioning in infancy or childhood. The German study also reported a negative association between postnatal PCB exposure and cognitive function in early childhood--a result that had not been found in previous studies. Only one published study in North Carolina (USA) has failed to find an association between PCB exposure and cognitive outcomes. Despite the fact that several more recent studies have used congener-specific analytic techniques, there have been only limited attempts to assess the role of specific PCB congeners or classes of congeners in mediating neurodevelopmental outcomes. From a statistical standpoint, attempts to determine the role of individual congeners in mediating outcomes are hampered by the fact that concentrations of most individual congeners are highly correlated with each other and with total PCBs. From a toxicological standpoint, these efforts are hampered by the fact that many of the PCB congeners present in human tissues have never been studied in the laboratory, and their relative potency to produce nervous system effects is unknown. More complete information on the health effects of various congeners or congener classes would allow more informed scientific and risk assessment decisions.

ObjectivesAttention deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurobehavioral disorder of childhood, yet its etiology is not well understood. In this review we present evidence that environmental chemicals, particularly polychlorinated biphenyls (PCBs) and lead, are associated with deficits in many neurobehavioral functions that are also impaired in ADHD.Data sourcesHuman and animal studies of developmental PCB or lead exposures that assessed specific functional domains shown to be impaired in ADHD children were identified via searches of PubMed using “lead” or “PCB exposure” in combination with key words, including “attention,” “working memory,” “response inhibition,” “executive function,” “cognitive function,” “behavior,” and “ADHD.”Data synthesisChildren and laboratory animals exposed to lead or PCBs show deficits in many aspects of attention and executive function that have been shown to be impaired in children diagnosed with ADHD, including tests of working memory, response inhibition, vigilance, and alertness. Studies conducted to date suggest that lead may reduce both attention and response inhibition, whereas PCBs may impair response inhibition to a greater degree than attention. Low-level lead exposure has been associated with a clinical diagnosis of ADHD in several recent studies. Similar studies of PCBs have not been conducted.ConclusionsWe speculate that exposures to environmental contaminants, including lead and PCBs, may increase the prevalence of ADHD.

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Each environmental exposure matrix contains a unique mixture of PCB congeners. Since several congener types have multiple and distinct biological actions, it is important to characterize congener profiles in exposure sources. The Fox River Environment and Diet Study (FRIENDS) is assessing the human health effects of consumption of PCB-contaminated fish from the Fox River in northeastern Wisconsin. Concurrent laboratory studies required the formulation of a dosing solution which closely mimicked the human PCB exposure from fish. PCB congener profiles from Fox River walleye were compared to profiles for various theoretical mixtures having different relative percentages of Aroclors by weight. The theoretical mixture which provided the best approximation of the Fox River fish PCB profile contained 35% 1242, 35% 1248, 15% 1254, and 15% 1260. A PCB mixture was formulated to match this theoretical construct, and the congener profile for the mixture of Aroclors was determined by capillary column gas chromatography with electron capture detection (GC/ECD). The relative percent of each congener was compared to the PCB congener profile of the theoretical Aroclor mixture and that for Fox River walleye. The specific congeners differed on average by 17% from the theoretical Aroclor mixture predicted values, and the specific congeners measured in the mixture were on average within 71% of those reported for Fox River fish. The mixture was found to have relatively low AhR activity but high RyR activity. Indirect comparisons suggest that in vivo toxicity was slightly greater than that for Aroclor 1254. This illustrates that Aroclor mixtures are useful for formulating dosing solutions which closely approximate actual environmental exposures.

The current study examined effects of chronic estradiol replacement on a prefrontally-mediated working memory task at different ages in a rodent model. Ovariectomized young, middle-aged, and old Long-Evans rats were given 5% or 10% 17β estradiol in cholesterol vehicle via Silastic implants and tested on an operant delayed spatial alternation task (DSA). The two estradiol exposed groups did not perform as well as the vehicle control group did. Deficits were present at all but the longest delay, where all groups including the vehicle control group performed poorly. Surprisingly, there was not a significant effect of age or an age by estradiol interaction, despite the fact that old rats had longer latencies to respond after both correct and incorrect lever presses. These data confirm our earlier finding that chronic estradiol treatment has an impairing effect on working memory as measured on DSA task. However, contrary to expectations, young, middle-aged and old rats were similarly impaired by chronic estradiol treatment; there were no indications of differential effects at different periods of the lifespan. Also contrary to expectations, there were no indications of a decline in DSA performance with advancing age. Overall, the results demonstrate that chronic estradiol exposure causes deficits in the DSA performance of ovariectomized female rats, not only in young adulthood, but also at older ages analogous to those at which hormone replacement therapy is commonly prescribed in humans.

An association between in utero polychlorinated biphenyl (PCB) exposure and impaired childhood intellectual functioning has been reported, but the potential impact of PCB exposure during adulthood on intellectual functioning has received little attention. We assessed the impact of PCBs and other fish-borne contaminants on intellectual functioning in older adults. The subjects were 49- to 86-year-old Michigan residents recruited from an existing cohort. Fish eaters ate > 24 lb of sport-caught Lake Michigan fish per year and non-fish eaters ate < 6 lb of Lake Michigan fish per year. A battery of cognitive tests including tests of memory and learning, executive function, and visual-spatial function was administered to 180 subjects (101 fish eaters and 79 non-fish eaters). Blood samples were analyzed for PCBs and 10 other contaminants. We evaluated cognitive outcomes using multiple regression. PCBs and dichlorodiphenyl dichloroethene (DDE) were markedly elevated in fish eaters. After controlling for potential confounders PCB, but not DDE, exposure was associated with lower scores on several measures of memory and learning. These included the Weschler Memory Scale verbal delayed recall (p = 0.001), the semantic cluster ratio (p = 0.006), and list A, trial 1 (p = 0.037), from the California Verbal Learning Test. In contrast, executive and visual-spatial function were not impaired by exposure to either PCBs or DDE. In conclusion, PCB exposure during adulthood was associated with impairments in memory and learning, whereas executive and visual-spatial function were unaffected. These results are consistent with previous research showing an association between in utero PCB exposure and impairments of memory during infancy and childhood.

Summary: Children in America today are at an unacceptably high risk of developing neurodevelopmental disorders that affect the brain and nervous system including autism, attention deficit hyperactivity disorder, intellectual disabilities, and other learning and behavioral disabilities. These are complex disorders with multiple causes—genetic, social, and environmental. The contribution of toxic chemicals to these disorders can be prevented. Approach: Leading scientific and medical experts, along with children’s health advocates, came together in 2015 under the auspices of Project TENDR: Targeting Environmental Neuro-Developmental Risks to issue a call to action to reduce widespread exposures to chemicals that interfere with fetal and children’s brain development. Based on the available scientific evidence, the TENDR authors have identified prime examples of toxic chemicals and pollutants that increase children’s risks for neurodevelopmental disorders. These include chemicals that are used extensively in consumer products and that have become widespread in the environment. Some are chemicals to which children and pregnant women are regularly exposed, and they are detected in the bodies of virtually all Americans in national surveys conducted by the U.S. Centers for Disease Control and Prevention. The vast majority of chemicals in industrial and consumer products undergo almost no testing for developmental neurotoxicity or other health effects. Conclusion: Based on these findings, we assert that the current system in the United States for evaluating scientific evidence and making health-based decisions about environmental chemicals is fundamentally broken. To help reduce the unacceptably high prevalence of neurodevelopmental disorders in our children, we must eliminate or significantly reduce exposures to chemicals that contribute to these conditions. We must adopt a new framework for assessing chemicals that have the potential to disrupt brain development and prevent the use of those that may pose a risk. This consensus statement lays the foundation for developing recommendations to monitor, assess, and reduce exposures to neurotoxic chemicals. These measures are urgently needed if we are to protect healthy brain development so that current and future generations can reach their fullest potential.

Estrogens have been shown to both enhance and impair cognitive function depending on several factors including regimen of hormone treatment, age of subject, and task attributes. In rodent models, estradiol tends to enhance spatial learning and impair response or cued learning, but effects on executive functions are less well-studied. In this experiment, spatial working memory and response inhibition were tested using delayed spatial alternation (DSA) and differential reinforcement of low rates of responding (DRL) tasks in ovariectomized rats that were given chronic estradiol via Silastic implants resulting in serum estradiol concentrations of 86.2±8.2 (SEM) pg/ml. Rats were tested for 25 days DSA with variable delays of 0, 3, 6, 9, and 18 seconds between lever presentations, followed by 30 days on a DRL-15s operant schedule. Estradiol-replaced rats showed a significantly lower proportion of correct responses on the DSA task compared to vehicle-implanted ovariectomized animals. On DRL, estradiol -treated rats showed a lower ratio of reinforced to non-reinforced presses. These data suggest that chronic estrogen exposure may impair rats’ abilities on measures of executive function including working memory and response inhibition.