Arsenic is a well-known lung carcinogen in humans. In 2006, IARC upgraded inorganic lead as a possible human carcinogen (2A). The aim of this thesis has been to evaluate the lung cancer mortality and incidence in long-term exposed primary lead smelter workers and also to estimate present exposures to arsenic and lead in relation to those occurring in the past. The basic cohort (N=3832 workers; hired before 1967 and followed up from 1950-1981; SMR comparisons with general and local reference populations) showed an excess of deaths for total mortality, malignant neoplasms (e.g. lung and stomach cancer), ischaemic heart diseases, and cerebrovascular diseases compared to the general population. In a subcohort of lead workers (N=437; regular blood lead sampling since 1950) only the raised SMR for lung cancer (162) was sustained. In a follow-up study of the basic cohort (N=3979), a subcohort of lead exposed workers (N=1992) was formed. The expected mortality in 1955-1987 and cancer incidence in 1958-1987 were calculated relative to county rates. A cumulative blood lead index (CBLI) was used for dose-response analyses. The lung cancer incidence was raised in the total cohort (SIR 2.8; 95 % CI 2.1 3.8). A higher lung cancer risk was observed in workers hired before 1950 (SIR 3.6; 95 % CI 2.6-5.0). The increased lung cancer risks were further elevated in the subcohort of lead exposed workers, especially in the highest exposed subgroup (SIR 5.1; 95 % 2.0-10.5; latency period of 15 y). No excesses of other malignancies were observed. The increased relative risks for lung cancer may have been caused by interactions between inorganic lead and other substances at the smelter, e.g. arsenic. To further analyze the effects from inorganic lead, two subcohorts of workers at the lead departments were formed from the original cohort (N=3979), one of 710 workers and the other of 383 workers. The lung cancer incidence was raised in both subcohorts (Lead subcohort 1; SIR 2.4; 95 % CI 1.2-4.5; Lead subcohort 2; SIR 3.6; 95 % CI 1.2-8.3). Among the 10 workers that had developed lung cancer in lead subcohort 1 all but one had a considerable exposure also to arsenic. Thus, a possible interaction effect between lead and arsenic may explain the increased lung cancer risks. To further elucidate the impact from lead and arsenic a case control study was undertaken. In the basic cohort (N=3979), 46 male workers had contracted respiratory malignancies. They were compared with 141 agematched male referents from the primary smelter by conditional logistic regression analysis using smoking habits, cumulative blood lead and air arsenic exposure as predictor variables. The lung cancer cases showed a significantly higher smoking rate than referents (Odds ratio, OR = 4.0; 95 % CI 1.6-10.1; p=0.003). When restricted to smokers, the cumulative arsenic air exposure index, but not the lead exposure indices, were significantly higher among the cases (OR=1.07; 95 % CI 1.02-1.11; p = 0.005). Accordingly, cumulative arsenic exposure and smoking were identified as significant risk factors for the development of lung cancer in the final analyses, while lead exposure was not a significant risk factor. However, inorganic lead still may play a minor role in the multifactorial genesis of lung cancer. These studies describe risks from exposures occurring from time periods before 1950 up to 1981. Because of the long latency period for lung cancer, exposures after 1970 probably have had limited impact on the reported results. Compared to the levels in the early 1970´s present exposures to arsenic are lower by a factor of ten or more and risks probably correspondingly lower.

Lead (Pb) is one of the most well known toxic heavy metals in human beings and animals, which leads to toxic neurological disorders, cognitive problems, learning and memory disabilities. Epidemiological studies revealed that chronic lead exposure is one of the environmental risk factors which may cause Alzheimer¡¦s Disease, which were speculated for the observation of cellular necrosis, apoptosis, and £]-amyloid deposition frequently occuring altogether after chronic lead exposure. Recent studies have shown that the £]-amyloid formed during autophagic turnover of APP-rich organelles supplied by both autophagy and endocytosis. Therefore, we will conduct the new perspective for studying the possible role of autophagy on amyloidogensis disorders after lead exposure. SH-SY5Y human neuroblastoma cells, used in this study, were differentiated to a neuronal phenotype by retinoic acid (RA) to the culture medium at 10 £gM for 1, 2, 3 and 4 days. Doses of lead acetate with of lead acetate were 5 £gM and applied to the neuronal culture and then cell viability measurement by MTT assay. The apoptotic effect of non-differentiation and differentiation neuroblastoma cells after lead exposure was determined by cleaved DNA fragments. Furthermore, APP, intracellular A£]1-40 and A£]1-42 expression were quantified by Real-time PCR and ELISA, respectively. The autophagy process and variation of total and phosphorylated mammalian target of rapamycin (mTOR) forms were determined after lead exposure in non-differentiation and differentiation neuroblastoma cells by western blot. The results indicate that lead exposure enhances autophagy response in both non-differentiation and differentiation SH-SY5Y cells, which might cause neuronal apoptosis associated with £]-amyloidgenesis. Otherwise, lead exposure resulted in the inhibition of mTOR signaling, which correlated with the autophagic process. Besides, in our studies, non-differentiated cells exhibited more toxic vulnerability than RA induced differentiated neuron is congruous to previous finding that lead exposure during fetal development might be a potential risk factor for AD in the adulthood.

In recent years, there has been a great deal of debate about the pervasiveness and persistence of neoliberal thinking. In the context of the post-2008 ‘great recession’ the resilience of neoliberalism is particularly confounding. To begin to unravel the ways in which neoliberalism is situated relative to risk, this study identifies an increasingly important neoliberal knowledge practice: malagnogenesis. Malagnogenesis is proposed herein as the production of ignorance that normalizes harm for and amongst marginalized populations. To shed light on the phenomena of malagnogenesis, this study investigated the history of leaded gasoline in the U.S. To that end, I followed the production of ignorance from the introduction of gasoline lead additives in the early 1920s to the contemporary discursive failure surrounding the impact that leaded gasoline has had on late 20th century urban crime rates. Finally, this study supported the hypothesis of malagnogenesis in academia via a survey of academics.

Indiana University-Purdue University Indianapolis (IUPUI) / Lead (Pb) is one of the most harmful and most abundant neurotoxins in the environment. Despite the extensive movement made to eradicate toxic levels of Pb in the environment, children, predominately in lower socioeconomic areas, are still exposed to varying levels of Pb. Human studies suggest that Pb exposure leads to altered drug consumption in adults by altering underlying neural mechanisms, specifically dopamine (DA) activity. However, there is limited research on this at blood Pb levels below 10 μg/dL, levels often seen in children growing up in neighborhoods located in old industrial and urban areas. To model how early-life low-level Pb exposure effects DA-dependent behaviors associated with addiction in adulthood, we used C57BL/6J mice. Litters were weaned at PND 21 and assigned to either a three-week history of 30 parts per million (ppm) Lead (IV) Acetate exposure or a control condition of 0 ppm Pb in DI drinking water. After the Pb exposure period, mice were switched to regular tap water until they reached adulthood. Afterward, separate animals were tested in one of three experiments: two-bottle choice alcohol preference drinking, alcohol-induced behavioral sensitization (EBS), and cocaine-induced behavioral sensitization (CBS). In experiment 1, our hypothesis was met, and both male and female mice with a prior Pb exposure displayed significantly higher alcohol intake and preference scores over the three-week period than control mice. In experiment 2, there were no differences in EBS and no evidence of EBS in any of the groups. However, there was an increased acute response to 2.0 g/kg EtOH in the Pb-exposed chronic group as compared to the control animals. Lastly, in experiment 3, Pb-exposed animals in the chronic cocaine group were more sensitive to the effects of cocaine (10 mg/kg) across days than the controls, both the acute cocaine groups and both saline control groups. Thus, with these experiments, we concluded that low levels of developmental Pb exposure might be targeting DA in the reward pathway, which is essential for alcohol intake and drug sensitization.

OBJECTIVES: Despite continued efforts to decrease environmental lead exposure, it remains a public health concern in the U.S. The aim of this study was to investigate the influence of lead exposure on dental caries risk among different populations. METHODS: We used data from Detroit Dental Health Project (DDHP), a cohort study of a representative sample of low-income African–American families in Detroit, Michigan, to investigate the influence of lead toxicity on dental caries risk among children, and to assess the effect of blood lead level on the caries experience among their caregivers. Data from Dental Longitudinal Study (DLS), a closed-panel prospective cohort study of oral health and aging, was used to assess the cross-sectional and longitudinal relationships between bone lead level as a cumulative measure of lead exposure and dental caries among older men. The outcome measure for cross-sectional analyses was dmfs/DMFS, which is the number of decayed surfaces, missing, and filled surfaces for each subject. Then adjusted new dmfs/DMFS increments were used for the longitudinal analyses. Descriptive and bivariate analyses were conducted on dental caries outcome by lead biomarkers. Multiple regression and GEE models were conducted controlling for confounding. RESULTS: History of lead toxicity (≥ 10µg/dl) and children’s caries risk was significantly associated in both cross-sectional analysis (PR = 1.50, p-value=0.003) and longitudinal analysis (IRR= 1.36, p-value=0.02). These associations were independent of confounding factors such as age, brushing frequency, soda consumption, income, and child and caregiver’s caries experience. On other hand, no significant associations were found between blood lead level and dental caries experience among African American adults (β=2.3, p-value=0.5), nor between high tibia/patella lead level and dental caries incident among older adult (β=0.1, p-value=0.7 for tibia, and β=0.3, p-value=0.1 for patella) . CONCLUSION: The results suggest that children with a history of lead toxicity are at a higher risk of developing dental caries compared to other children. However, there is no significant association between lead exposure and dental caries among adults. Therefore, children with a history of lead toxicity should be given special consideration in caries risk assessment and caries prevention programs. / 2019-09-26T00:00:00Z

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<p>This dissertation examines lead exposure and effects across the lifespan among vulnerable populations. The vulnerable population that this dissertation focuses on are the elderly, newcomers to the US, which represents immigrants, as well as adolescents and women of childbearing age. The first chapter gives an introduction and highlights the history of lead as it relates to environmental and occupational exposure having deleterious effects on the human system. The second chapter highlights the association between blood lead level and subsequent Alzheimer’s disease (AD) mortality in those 65 years and older. Chapter 3 looks at whether length of time in the United States is a predictor of adolescent and adult blood lead levels. The fourth chapter assesses whether early life lead exposure is associated with AD mortality later in life. Adaptations of Chapter 2 and Chapter 3 of this dissertation have been submitted for publication.</p><p>Chapter 2 presents a longitudinal study of 8080 elders (≥60 years) with BLL data from the 1999-2008 National Health and Nutrition Examination Survey, where mortality was determined from linked 1999-2014 National Death Index data. In this study, a causal diagram presented causal assumptions and identified a sufficient set of confounders: age, sex, poverty, race/ethnicity, and smoking. Cox proportional hazard models were used to determine the association between BLL and subsequent AD mortality. Impacts of competing risks and design effect were also assessed. Adjusted hazard rate ratio (HRR) and 95% confidence interval (CI) were reported. Results showed that those with BLL of 1.5 μg/dL and 5 μg/dL had 1.2 (95% CI: 0.70, 2.1) and 1.4 (95% CI: 0.54, 3.8) times the rate of AD mortality compared to those with BLL of 0.3 μg/dL, respectively, after accounting for competing risks. Adjusted HRRs were 1.5 (95% CI 0.81, 2.9) and 2.1 (95% CI 0.70, 6.3), respectively, after considering design effect. This longitudinal study demonstrated a positive, albeit statistically non-significant association between BLL and AD mortality, after adjustment for competing risks or design effect.</p><p>Chapter 3 included cross-sectional 1580 women of childbearing age (15-45 years) and 5933 men and women (≥15 years) from the 2013-2016 United States National Health and Nutrition Examination Survey. Linear regression models adjusted for race/ethnicity, education, blood cotinine, age, sex (as appropriate) and accounted for complex survey design. Results showed that women of childbearing age who have lived 0-4 years in the US have, on average, a 43% (95% confidence interval (CI): 31%, 56%) higher BPb compared to women born in the US. Corresponding results for all adults and adolescents was 40% (95% CI: 28%, 51%). Similar, statistically significant, results were observed for other time periods (5-9 years, 10-19 years, and ≥20 years); the magnitude of the association decreased with increasing time in the US. Higher BPb was also significantly associated with Asian (vs. white), lower education, higher age, and male (vs. female).</p><p>Chapter 4 is an ecologic study utilizing data from the United States Census Bureau and American Fact Finder. This ecologic study uses publicly available data from the 1930s US census and the Centers for Disease Control and Prevention to compare estimated historic lead exposure with AD mortality rates among US states and Indiana counties. Occupations were assigned a numeric weight based on the likelihood of lead exposure. The proportion of workers in each occupation multiplied by this weight was used to create a historic lead exposure index; quintiles of this index were used in analyses. AD mortality rates among persons ≥ 65 years old from 1999-2016 were obtained from the Centers for Disease Control and Prevention. The relationship between the historic exposure index and mortality was evaluated using correlation coefficients and linear regression models adjusting for age, sex, education, socioeconomic status (SES). Maps to characterize spatial pattern of historic lead exposure and AD mortality were completed using Geographic Information System (GIS) spatial analysis tools for the U.S. at state level and at county level for Indiana. Results showed that among states, the average AD mortality rate was 202.2 per 100,000 (SD=44.4). Within Indiana, the average AD mortality rate was 209.6 per 100,000 (SD= 64.9). Among Indiana counties, the unadjusted model shows an association of higher HEI with higher AD mortality, with the fifth quintile reaching statistical significance. Results for the adjusted model were not statistically significant. Results for US states for both unadjusted and adjusted regression models show that the third, fourth, and fifth quintiles of the historic exposure index were associated with a significantly lower AD mortality rate when compared to the lowest quintile.</p><p>Conclusion: The first study, using a longitudinal design, shows a positive but non-significant association between BLL and subsequent AD mortality after adjustments for competing risks or design effects. The second study, using a cross-sectional design, showed that newcomers to the US may be a population at higher risk for elevated BPb. The third, ecological study, did not find any significant association between historic lead exposure and AD mortality rates for Indiana counties, however there was a significant association of higher historic lead exposure index with lower AD mortality rates for states in the US.</p>

<p>Lead (Pb) is one of the most harmful and most abundant neurotoxins in the environment. Despite the extensive movement made to eradicate toxic levels of Pb in the environment, children, predominately in lower socioeconomic areas, are still exposed to varying levels of Pb. Human studies suggest that Pb exposure leads to altered drug consumption in adults by altering underlying neural mechanisms, specifically dopamine (DA) activity. However, there is limited research on this at blood Pb levels below 10 μg/dL, levels often seen in children growing up in neighborhoods located in old industrial and urban areas. To model how early-life low-level Pb exposure effects DA-dependent behaviors associated with addiction in adulthood, we used C57BL/6J mice. Litters were weaned at PND 21 and assigned to either a three-week history of 30 parts per million (ppm) Lead (IV) Acetate exposure or a control condition of 0 ppm Pb in DI drinking water. After the Pb exposure period, mice were switched to regular tap water until they reached adulthood. Afterward, separate animals were tested in one of three experiments: two-bottle choice alcohol preference drinking, alcohol-induced behavioral sensitization (EBS), and cocaine-induced behavioral sensitization (CBS). In experiment 1, our hypothesis was met, and both male and female mice with a prior Pb exposure displayed significantly higher alcohol intake and preference scores over the three-week period than control mice. In experiment 2, there were no differences in EBS and no evidence of EBS in any of the groups. However, there was an increased acute response to 2.0 g/kg EtOH in the Pb-exposed chronic group as compared to the control animals. Lastly, in experiment 3, Pb-exposed animals in the chronic cocaine group were more sensitive to the effects of cocaine (10 mg/kg) across days than the controls, both the acute cocaine groups and both saline control groups. Thus, with these experiments, we concluded that low levels of developmental Pb exposure might be targeting DA in the reward pathway, which is essential for alcohol intake and drug sensitization.</p>