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Indiana University-Purdue University Indianapolis (IUPUI) / Environmental exposure to lead (Pb) and cannabis use are two of the largest public health issues facing modern society in the United States and around the world. Exposure to Pb in early life has been unequivocally shown to have negative impacts on development, and recent research is mounting showing that it may also predispose individuals for risk of developing substance use disorders (SUD). At the same time, societal and legal attitudes towards cannabis (main psychoactive component delta-9-tetrahydrocannabinol) have been shifting, and many American states have legalized the recreational use of cannabis. It is also the 3rd most widely used drug of abuse in the US, and rates of cannabis use disorder are on the rise. This thesis sets out to establish whether there is a link between early life Pb exposure and later THC-related behavior in C57BL6/J mice, as has been demonstrated for other drugs of abuse. The first aim seeks to answer whether Pb exposure affects physiological THC sensitivity (as measured by the cannabinoid-induced tetrad). The second aim seeks to answer whether Pb exposure affects edible THC self-administration and the development of THC tolerance (also measured by the tetrad). It was hypothesized that Pb exposure would decrease THC sensitivity (Aim 1), would enhance THC self-administration (Aim 2), enhance the development of THC tolerance (Aim 2), and finally that sex-dependent effects of Pb-exposure and THC would be observed (Aims 1 & 2). These hypotheses ended up not being supported, but Aim 1 produced findings indicating that THC sensitivity was increased by Pb exposure, but only in female mice. Future research will hopefully be able to fully explore the implications of these findings.

Introduction. In 2006, a Peruvian environmental agency reported the presence of elevated blood lead levels (BLLs) in indigenous communities of the Corrientes river basin. This is a territory in the Peruvian Amazon where oil activity has been associated with serious environmental effects, with impact on an ongoing social conflict. This PhD project aimed to determine the lead sources, risk factors and pathways in children of these communities and to suggest control and prevention strategies. Given the arguments attributing the lead source to the oil activity pollution, the second objective was to clarify any potential connection between the two. This project was conducted by a collaborative research partnership with the regional health authorities and the community-based organization. The third objective was to characterize the challenges, facilitating factors and the lessons learned from the research process. Methods. Two epidemiological studies were conducted. Study I (2009) was carried out in three communities and study II (2010) in six communities with different levels of exposure to oil activity. The participants were children 0–17 years old. Data collection included: determination of BLLs, hemoglobin levels and anthropometric indicators, a risk factor questionnaire, an environmental assessment and a risk map. Data analysis included univariate, bivariate and multivariate logistic regression. Data for the third objective came from field notes, documents, interviews and a process of collective reflection. Results. Study I (n= 221) found no significant difference in the geometric mean(GM) BLLs between the communities exposed and not exposed to oil activity. Older age and being a boy were found as risk factors for BLLs ≥ 10 μg/dL. In study II (n= 346), age stratified logistic regression models indicated that children 0–3 years whose mothers had BLLs ≥ 10 μg/dL, children 0–6 years who played with pieces of lead and children 7–17 years who fished 3 times or more per weekor chewed pieces of lead to manufacture fishing sinkers had a significant increased risk of having BLLs ≥ 10 μg/dL. Children who lived in communities near oil battery facilities also had a significant increased risk of having BLLs ≥ 10 μg/dL. In both studies, environmental samples showed lead concentrations below reference levels. The challenges and facilitating factors identified focused on five interrelated themes: i) mutual trust, ii) multiple agendas, iii) equal participation, iv) competing research paradigms and v) complex and unexpected findings. Conclusions. Metal lead appeared to be the main source of exposure. Playing with pieces of lead and chewing pieces of lead to construct fishing sinkers appeared to be pathways of exposure for children aged 0–6 years and 7–17 years, respectively. Mothers’ BLLs > 10 μg/dL was a risk factor for BLLs > 10 μg/dL in children aged 0–3 years. Living in a community with high exposure to oil activity was a risk factor for BLLs > 10 μg/dL. The identified connection with oil activity was the proximity of communities to oil battery facilities and thus greater access to lead from cables and other industrial waste. Despite the numerous challenges, participatory research appears to be the most appropriate approach for this type of context. The study findings led us to recommend:i) a comprehensive community-based lead control and prevention plan,ii) the introduction of substitute non-harmful material(s) for fishing sinkers and iii) secure containment of the oil company’s waste deposits. / Introducción. En el 2006, una agencia ambiental del Perú informó de la presenciade niveles elevados de plomo sanguíneo en las comunidades indígenas dela cuenca del río Corrientes. Este es un territorio en la Amazonía peruana, dondela actividad petrolera ha sido asociada con graves efectos ambientales, originandoun continuo conflicto social.Este proyecto de tesis doctoral tuvo como objetivo determinar las fuentes, factoresde riesgo y vías de exposición de plomo en niños de estas comunidades paraproponer estrategias de control y prevención. Teniendo en cuenta previos argumentosque relacionaban la exposición de plomo con la contaminación por laactividad petrolera, el segundo objetivo fue esclarecer cualquier conexión entreambos. Este proyecto se condujo con la participación de miembros de la DirecciónRegional de Salud de Loreto (DIRESA Loreto) y de la organización indígenaFECONACO. El tercer objetivo fue caracterizar los desafíos, las oportunidades ylos aprendizajes del proceso participativo.Métodos. Se condujeron dos estudios epidemiológicos. El estudio I (2009) sedesarrolló en tres comunidades y el estudio II (2010) en seis comunidades condiferentes niveles de exposición a la actividad petrolera. Los participantesfueron niños de 0–17 años. La recolección de datos incluyó: determinación deplomo sanguíneo, de niveles de hemoglobina y de indicadores antropométricos,un cuestionario de factores de riesgo, una evaluación ambiental y un mapa deriesgo. El análisis de datos incluyó análisis univariado, bivariado y multivariadode regresión logística. Para el tercer objetivo, los datos provinieron de notas decampo, documentos oficiales, entrevistas informales y un proceso de reflexióncolectiva.Resultados. En el estudio I (n = 221) no se encontró diferencia estadísticamentesignificativa entre las medias geométricas de los niveles de plomo sanguíneo delas comunidades expuestas y no expuestas a la actividad petrolera. Los niños degénero masculino y los del grupo etario de mayor edad tuvieron un riesgo significativamentemayor a presentar niveles de plomo sanguíneo > 10 μg/dL. Enel estudio II (n = 346), los modelos estratificados por edad indicaron que losniños de 0–3 años cuyas madres tenían niveles de plomo > 10 μg/dL, los niñosde 0–6 años que jugaban con piezas de plomo y los niños de 7–17 años que pescaban3 veces o más por semana o masticaban piezas de plomo para fabricarpesas de pescar tenían un riesgo significativamente mayor de presentar nivelesde plomo sanguíneo > 10 μg/dL. Los niños que vivían en comunidades cercanasa las baterías de petróleo también tuvieron un riesgo significativamente mayora presentar plomo sanguíneo > 10 μg/dL. Las muestras ambientales en ambosestudios mostraron concentraciones de plomo por debajo de los niveles de referencia.En cuanto al proceso de investigación, los desafíos y oportunidades másimportantes se centraron en cinco temas interrelacionados: i) la confianza mutua,ii) múltiples agendas, iii) participación equitativa, iv) competencia de paradigmasen la investigación y v) diseminación de resultados complejos e inesperados.Conclusiones. La fuente de exposición principal sería el plomo metálico. Jugarcon piezas de piezas de plomo y masticar piezas de plomo para la construcciónde pesas de pescar serían vías de exposición para los niños de 0–6 años y 7–17años, respectivamente. Niveles de plomo sanguíneo > 10 μg/dL en las madressería un factor de riesgo para presentar niveles de plomo sanguíneo > 10 μg/dLen niños de 0–3 años. Vivir en una comunidad con alta exposición a la actividadpetrolera sería también un factor de riesgo para presentar niveles de plomo sanguíneo> 10 μg/dL. La conexión con la actividad petrolera parece estar en laproximidad de las comunidades a las baterías del petróleo y por ende, el mayoracceso al plomo proveniente de cables y otros residuos industriales.A pesar de los varios desafíos, la investigación participativa parece ser el enfoquemás apropiado para este tipo de contextos. Los hallazgos nos llevaron a recomendar:i) un programa comunitario de control y prevención de plomo, ii) laintroducción de pesas de pescar de materiales seguros, alternativos al plomo yiii) el control de la disposición de residuos de la actividad petrolera.

Lead is a toxic heavy metal associated with adverse health effects ranging from developmental neurotoxicity to reproductive effects. While lead affects people of all ages, infants and children are the most vulnerable and susceptible to the neuro-developmental effects of lead exposure. Maternal blood lead concentrations that do not produce clinical toxicity on pregnant women have been linked to adverse offspring development. Observed reproductive effects to low lead levels during pregnancy include the risk of spontaneous abortions, effects on birth weight and preterm birth. There are particular concerns with regard to reductions in IQ scores. Research evidence suggests that an incremental increase in blood lead levels of 1 µg/dL is associated with approximately 1 IQ point deficit. Of particular concern is that currently no threshold has been observed or exists for developmental neurotoxicity to the chronic low lead exposures levels. While the developed countries have built evidence for lead exposure sources, have identified the most vulnerable groups to lead exposure, and have instituted control actions for lead exposure, it is not the case in developing countries such as Botswana. Currently, there is very little knowledge about the potential sources of lead exposure among different population groups not only in Botswana but also in most developing nations. There is also an evident limited knowledge on the behaviours and practices of different population groups that could potentially expose them to lead in developing countries. This thesis explores the following questions: i) Are there specific risk behaviours and practices peculiar to pregnant women in Botswana that could potentially expose them to lead? ii) What are the environmental lead concentration levels and their potential to expose pregnant women? iii)What are the blood lead concentrations at each stage of pregnancy and after delivery in Botswana and, iv) Can we use the information from these three questions to predict lead exposure levels during pregnancy and after delivery? v) Can we use the new information to a develop a policy dissemination brief to inform policy on lead exposure sources in Botswana, develop guidelines for health professionals for assessing and screening lead exposure levels during pregnancy and after delivery, develop an awareness leaflet for lead education? To address the specific risk behaviour and practices of pregnant women, a comprehensive validated risk assessment questionnaire was administered among 142 pregnant women during the first trimester of pregnancy (defined as 8-12 weeks) in four villages of different geographical settings and nomenclature (small/rural, major and semi urban). For purposes of this work the validation process involved obtaining information (from experts in the field and communities) relevant to the purposes of the study and to confirm that the tools employed for collection of data in all trimesters were suitable in terms of both construct and content. Data was collected between September 2009 and February 2010. To address potential environmental sources of lead exposure during pregnancy soil (n=28), water (n=28) and traditional cosmetic clay - letsoku (n=3) samples were collected in November 2010, February 2011 and May 2011 from the homes and in the vicinity of the study population to determine lead concentrations. To know baseline blood lead levels at each stage of pregnancy, blood samples were collected from September 2009 to February 2011 from pregnant women between weeks 8-12 (first trimester, n=137), 20-24 (second trimester n=126) and weeks 34-36 (third trimester n=106). Blood lead levels of women who completed the entire study from trimester on until after delivery (n=63) were then used to construct blood lead prediction models using statistical models. Pregnant women in the study area ingested non-food items such as soil, match sticks, pencil, chalk and animal feed such as bone meal (86%). Women applied used and unused car oils (in particular brake fluid) and other harmful substances for “treatment of skin conditions and for beautification purposes (74%). Older women (defined as 35 years in this study) were at a significantly higher risk to ingest soils (p<0.01). Mean (±SEM) lead concentrations in water exceeded the WHO drinking water quality standards nineteen fold (0.19±0.019 ppm (n=28) Major villages, had significantly higher Pb concentrations (p<0.05) in soils and water compared to small villages. Mean blood lead levels (±SEM) for the first, second and third trimesters were 1.96(±0.14)µg/dL, 2.49(±0.17) µg/dL, 2.66(±0.19) µg/dL respectively. Blood lead levels increases from the first to third trimester ranged from 1.6-5%. Blood lead concentrations significantly differed among locations (p<0.01). The highest concentrations were observed in women from smaller villages that were poorer (p<0.02). Pica, multiple risk behaviours/practices (engaging in two or more risk behaviours/practices), trimester of pregnancy, poor food supplementation and diet were predictors of blood lead levels ≥ 2µg/dL. There was a dose response relationship between supplement intake and an increase in blood lead levels. These findings suggest that pregnant women and their unborn babies could potentially be exposed to lead because of the environment in which they live, their economic status, lifestyle, behaviors and practices. Drinking water is a potential threat for lead exposure, not only among pregnant women, but other vulnerable groups such as infants and children. This study is the first in Botswana and one of the few in Africa to investigate lead exposure sources at each stage of pregnancy and after delivery. It is also the first to identify new potential lead exposure behaviors and practices such as the application of auto oils by pregnant women for treatment of skin diseases. The findings suggest the need to train health workers and equip them with the skills and knowledge to assess and screen women who could potentially be exposed to lead. Further, pregnant women need to be sensitized on potential lead exposure sources, to prevent lead poisoning. This study has been able to use the results to develop a policy brief for disseminating the results to decision makers, guidelines for utilization by health workers to screen lead exposure levels and an awareness leaflet for pregnant women. These have been validated and pretested at community and Government levels. / Thesis (PhD)--University of Pretoria, 2013. / School of Health Systems and Public Health (SHSPH) / Unrestricted

Lead neurotoxicity is considered a problem in young children and the long-term effects of lead exposure on them have yet to be determined. Studies have been completed to determine how lead exposure has affected children through their most important developmental stages. However, there is a lack of research to uncover any long-term effects lead may have as children enter adulthood. The purpose of this study was to determine long-term effects of lead exposure on IQ. The theoretical foundation for this study is the Cattell Horn Carroll theory of intelligence, which is based on fluid (novel experiences) and crystallized (previous experiences) intelligence. This study focused on individuals who were exposed to lead as children and are now young adults (ages 18-25). These individuals were part of a class action lawsuit and referred to a clinical psychologist from a private clinic who conducted IQ testing. In this non-experimental quantitative study, a multiple regression analysis was conducted on secondary data. Independent variables were first and last blood lead and Appearance, Pulse, Grimace, Activity, and Respiration scores as indicated from medical records. The dependent variables were the perceptual reasoning index, and verbal comprehension index of the WAIS-IV administered by a licensed clinical psychologist. The results of this study showed that childhood lead toxicity did not predict IQ scores in young adulthood. More research needs to be completed so that governmental agencies will have more information to be proactive in creating and changing policies around the use of lead in products that people use daily. This could lead to positive social change by placing an emphasis on early identification and treatment of lead exposure.

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<p>Environmental exposure to lead (Pb) and cannabis use are two of the largest public health issues facing modern society in the United States and around the world. Exposure to Pb in early life has been unequivocally shown to have negative impacts on development, and recent research is mounting showing that it may also predispose individuals for risk of developing substance use disorders (SUD). At the same time, societal and legal attitudes towards cannabis (main psychoactive component delta-9-tetrahydrocannabinol) have been shifting, and many American states have legalized the recreational use of cannabis. It is also the 3^rdmost widely used drug of abuse in the US, and rates of cannabis use disorder are on the rise. This thesis sets out to establish whether there is a link between early life Pbexposure and later THC-related behavior in C57BL6/J mice, as has been demonstrated for other drugs of abuse. The first aim seeks to answer whether Pbexposure affects physiological THC sensitivity (as measured by the cannabinoid-induced tetrad). The secondaimseeks to answer whether Pbexposure affects edible THC self-administration and the development of THC tolerance (also measured by the tetrad).It was hypothesized that Pbexposure would decrease THC sensitivity (Aim 1), would enhance THC self-administration (Aim 2), enhance the development of THC tolerance (Aim 2), and finally that sex-dependent effects of Pb-exposure and THC would be observed (Aims 1 & 2). These hypotheses ended up not being supported, but Aim 1 produced findings indicating that THC sensitivity was increased by Pbexposure, but only in female mice. Future researchwill hopefully be able to fully explore the implications of these findings.</p>

A exposição a agentes químicos neurotóxicos pode concorrer para o desenvolvimento ou potencialização de dificuldades de aprendizagem. A investigação dos níveis de concentração de metais pesados em escolares com tais dificuldades pode auxiliar no planejamento terapêutico, bem como orientar órgãos de saúde competentes para promoção de prevenção e de desintoxicação. Foi realizado um estudo com o objetivo de verificar as concentrações remotas de chumbo em escolares com dificuldades de aprendizagem, a fim de avaliar a prevalência de exposição precoce a este agente, bem como correlacionar os níveis encontrados com resultados de desempenhos em avaliações de processamento fonológico, leitura, escrita e aritmética, além de descrever estatisticamente a amostra quanto a aspectos relevantes do histórico clínico e identificar os bairros de origem ao nascimento. Participaram escolares na faixa etária de 9 a 14 anos, regularmente matriculados no Ensino Básico de instituições públicas ou privadas do município de Bauru (SP) e região, em atendimento na Clínica de Linguagem Escrita da FOB-USP. Foram utilizadas amostras de esmalte dentário superficial como biomarcador de exposição remota ao chumbo. Foram realizadas análises por espectrometria de absorção atômica de forno de grafite (GF AAS) para determinação do chumbo e espectrometria de emissão óptica com plasma indutivamente acoplado (ICP OES) para determinação do fósforo, necessário para o cálculo da massa de esmalte. O estudo teve 17 participantes. Os resultados indicam a prevalência de 100% de exposição precoce ao chumbo, média da concentração de 46,56 g Pb/g esmalte, DP = 47,09. Não houve correlações estatisticamente significativas com os desempenhos avaliados. Quanto ao perfil amostral, as meninas representam 17,6% e os meninos 82,4%. Um total de 35,3% dos participantes sofreram intercorrências gestacionais ou neonatais, 23,5% tem QI limítrofe ou rebaixado, 94,1% tem histórico de distúrbios de linguagem oral, 41,2% alterações psicomotoras, 5,9% diagnosticados com TDAH. A análise descritiva qualitativa dos bairros de origem revela que a distribuição dos mesmos está dispersa pelo município, além de participantes de outras localidades da região. / Exposure to neurotoxic chemical agents may contribute to the development or enhancement of learning disabilities. The investigation of concentration levels of heavy metals in schoolchildren with such difficulties can aid in therapeutic planning as well as guide competent health agencies to promote prevention and detoxification. A study was carried out with the objective of verifying the remote concentrations of lead in students with learning disabilities in order to evaluate the prevalence of early exposure to this agent, as well as to correlate the levels found with results of performances in phonological processing evaluations, reading, writing and arithmetic, in addition to statistically describing the sample regarding relevant aspects of clinical history and identifying origin neighborhoods at birth. Participants were students aged 9 to 14 years, regularly enrolled in Basic Education of public or private institutions of the municipality of Bauru (SP) and region, attending the Clinic of Written Language of FOB-USP. Surface dental enamel samples were used as a biomarker for remote lead exposure. Analyzes were performed by atomic absorption spectrometry of graphite furnace (GF AAS) for determination of lead and inductively coupled plasma optical emission spectrometry (ICP OES) for determination of phosphorus, necessary for the calculation of enamel mass. The study had 17 participants. The results indicate the prevalence of 100% early exposure to lead, mean concentration of 46.56 g Pb / g enamel, SD = 47.09. There were no statistically significant correlations with the evaluated performances. The sample profile reveals that girls represent 17.6% and boys 82.4%. A total of 35.3% of the participants had gestational or neonatal intercurrences, 23.5% had borderline or reduced IQ, 94.1% had a history of oral language disorders, 41.2% had psychomotor disturbances, 5.9% had ADHD. The qualitative descriptive analysis of the origin neighborhoods reveals that its distribution is dispersed by the municipality, besides participants of other localities of the region.