Genotoxicity in humans exposed to arsenic, lithium, and boron in drinking water in the Bolivian Andes-A cross sectional study.

Elevated concentrations of arsenic, lithium and boron in drinking water have already been reported in Bolivia. Arsenic is known to cause genotoxicity but that caused by lithium and boron is less well known. The aim of the present cross-sectional study was to evaluate potential genotoxic effects of exposure to arsenic, while considering exposure to lithium and boron and genetic susceptibility. Women (n = 230) were recruited in villages located around Lake Poopó. Exposure to arsenic was determined as the sum of concentrations of arsenic metabolites inorganic arsenic, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) in urine. Exposure to lithium and boron was determined based on their concentrations in urine. Genetic susceptibility was determined by GSTM1 (glutathione S-transferase-mu-1) and GSTT1 (glutathione S-transferase-theta-1) null genotypes and AS3MT (Arsenite Methyltransferase) rs3740393. Genotoxicity was measured in peripheral blood leukocytes using the comet assay. The geometric means of arsenic, lithium, and boron concentrations were 68, 897, and 3972 µg/L, respectively. GSTM1 and GSTT1 null carriers had more DNA strand breaks than gene carriers (p = .008, p = .005). We found no correlation between urinary arsenic and DNA strand breaks (rS = .03, p = .64), and only a weak non-significant positive association in the adjusted multivariate analysis (ß = .09 [-.03; .22], p = .14). Surprisingly, increasing concentrations of lithium in urine were negatively correlated with DNA strand breaks (rS = -.24, p = .0006), and the association persisted in multivariate analysis after adjusting for arsenic (ß = -.22 [-.36; -.08], p = .003). We found no association between boron and DNA strand breaks. The apparent protective effect of lithium merits further investigation.

Genetic factors for differentiated thyroid cancer in French Polynesia: new candidate loci.

Background: Populations of French Polynesia (FP), where France performed atmospheric tests between 1966 and 1974, experience a high incidence of differentiated thyroid cancer (DTC). However, up to now, no sufficiently large study of DTC genetic factors in this population has been performed to reach definitive conclusion. This research aimed to analyze the genetic factors of DTC risk among the native FP populations. Methods: We analyzed more than 300 000 single nucleotide polymorphisms (SNPs) genotyped in 283 DTC cases and 418 matched controls born in FP, most being younger than 15 years old at the time of the first nuclear tests. We analyzed the genetic profile of our cohort to identify population subgroups. We then completed a genome-wide analysis study on the whole population. Results: We identified a specific genetic structure in the FP population reflecting admixture from Asian and European populations. We identified three regions associated with increased DTC risk at 6q24.3, 10p12.2, and 17q21.32. The lead SNPs at these loci showed respective p-values of 1.66 × 10-7, 2.39 × 10-7, and 7.19 × 10-7 and corresponding odds ratios of 2.02, 1.89, and 2.37. Conclusion: Our study results suggest a role of the loci 6q24.3, 10p12.2 and 17q21.32 in DTC risk. However, a whole genome sequencing approach would be better suited to characterize these factors than genotyping with microarray chip designed for the Caucasian population. Moreover, the functional impact of these three new loci needs to be further explored and validated.

Assessment of Differentiated Thyroid Carcinomas in French Polynesia After Atmospheric Nuclear Tests Performed by France.

Importance: Due to the amount of iodine 131 released in nuclear tests and its active uptake by the thyroid, differentiated thyroid carcinoma (DTC) is the most serious health risk for the population living near sites of nuclear tests. Whether low doses to the thyroid from nuclear fallout are associated with increased risk of thyroid cancer remains a controversial issue in medicine and public health, and a misunderstanding of this issue may be associated with overdiagnosis of DTCs. Design, Setting, and Participants: This case-control study was conducted by extending a case-control study published in 2010 that included DTCs diagnosed between 1984 and 2003 by adding DTCs diagnosed between 2004 and 2016 and improving the dose assessment methodology. Data on 41 atmospheric nuclear tests conducted by France between 1966 and 1974 in French Polynesia (FP) were assessed from original internal radiation-protection reports, which the French military declassified in 2013 and which included measurements in soil, air, water, milk, and food in all FP archipelagos. These original reports led to an upward reassessment of the nuclear fallout from the tests and a doubling of estimates of the mean thyroid radiation dose received by inhabitants from 2 mGy to nearly 5 mGy. Included patients were diagnosed from 1984 to 2016 with DTC at age 55 years or younger and were born in and resided in FP at diagnosis; 395 of 457 eligible cases were included, and up to 2 controls per case nearest by birthdate and matched on sex were identified from the FP birth registry. Data were analyzed from March 2019 through October 2021. Exposure: The radiation dose to the thyroid gland was estimated using recently declassified original radiation-protection service reports, meteorological reports, self-reported lifestyle information, and group interviews of key informants and female individuals who had children at the time of these tests. Main Outcomes and Measures: The lifetime risk of DTC based on Biological Effects of Ionizing Radiation (BEIR) VII models was estimated. Results: A total of 395 DTC cases (336 females [85.1%]; mean [SD] age at end of follow-up, 43.6 [12.9] years) and 555 controls (473 females [85.2%]; mean [SD] age at end of follow-up, 42.3 [12.5] years) were included. No association was found between thyroid radiation dose received before age 15 years and risk of DTC (excess relative risk [ERR] per milligray, 0.04; 95% CI, -0.09 to 0.17; P = .27). When excluding unifocal noninvasive microcarcinomas, the dose response was significant (ERR per milligray, 0.09; 95% CI, -0.03 to 0.02; P = .02), but several incoherencies with the results of the initial study reduce the credibility of this result. The lifetime risk for the entire FP population was 29 cases of DTC (95% CI, 8-97 cases), or 2.3% (95% CI, 0.6%-7.7%) of 1524 sporadic DTC cases in this population. Conclusions and Relevance: This case-control study found that French nuclear tests were associated with an increase in lifetime risk of PTC in FP residents of 29 cases of PTC. This finding suggests that the number of thyroid cancer cases and the true order of magnitude of health outcomes associated with these nuclear tests were small, which may reassure populations of this Pacific territory.

Evaluating post-treatment Loa loa microfilarial densities to classify serious adverse events caused by ivermectin: a retrospective analysis.

BACKGROUND: The elimination of onchocerciasis requires increasing ivermectin treatment coverage in communities hypoendemic for onchocerciasis. In areas where loiasis is co-endemic, this approach is complicated by the risk of serious adverse events following treatment with ivermectin in individuals with a high Loa loa microfilarial density (MFD). We aimed to evaluate the extent to which the pre-treatment MFD can be inferred from post-treatment MFDs. METHODS: For this retrospective analysis, we used data from seven clinical or community trials (six were used for the main analysis and one for the secondary analysis) conducted in Cameroon, in which MFDs were measured both before and after (within 14 days) receiving a single dose of ivermectin (150-200 µg/kg bodyweight). The primary objective was to establish the receiver operating characteristic curves and the corresponding area under the curve statistics of MFD measured after treatment to classify pre-treatment MFD (MFDD0) according to common risk thresholds of serious adverse events. We assessed the performance of post-treatment MFD to accurately classify MFDD0 according to commonly used thresholds using bootstrap procedures. FINDINGS: 281 individuals with MFD measurements available before and 3-10 days after ivermectin treatment were enrolled. Our results show that an MFD of more than 3500 L loa microfilariae per mL of blood (mf per mL) 3 or 4 days after treatment indicates a 68·6% chance (positive predictive value) of an MFDD0 of more than 20 000 mf per mL. An MFD of more than 3500 mf per mL at day 5-10 corresponds to a 72·2% chance of having an MFDD0 of more than 20 000 mf per mL. Conversely, an MFD of less than 2500 microfilariae per mL at day 3-4 or day 5-10 corresponds to a probability of 92·3% or 92·8% (negative predictive value) of having MFDD0 of less than 20 000 mf per mL. An MFD less than 1500 mf per mL on days 3-4 after treatment was associated with a 78·3% probability of having an MFDD0 less than 8000 mf per mL; this probability increased to 89·6% on days 5-10 after treatment. INTERPRETATION: The MFD threshold of 1000 mf per mL within 1 month of treatment, which is commonly used to attribute the occurrence of a serious adverse event to ivermectin, should be revised. In this study, we present tables that can help to assess this attributability as part of mass or individual treatments. FUNDING: None.

Human adaptation to arsenic in Bolivians living in the Andes.

Humans living in the Andes Mountains have been historically exposed to arsenic from natural sources, including drinking water. Enzymatic methylation of arsenic allows it to be excreted more efficiently by the human body. Adaptation to high-arsenic environments via enhanced methylation and excretion of arsenic was first reported in indigenous women in the Argentinean Andes, but whether adaptation to arsenic is a general phenomenon across native populations from the Andes Mountains remains unclear. Therefore, we evaluated whether adaptation to arsenic has occurred in the Bolivian Andes by studying indigenous groups who belong to the Aymara-Quechua and Uru ethnicities and have lived in the Bolivian Andes for generations. Our population genetics methods, including genome-wide selection scans based on linkage disequilibrium patterns and allele frequency differences, in combination with targeted and whole-genome sequencing and genotype-phenotype association analyses, detected signatures of positive selection near the gene encoding arsenite methyltransferase (AS3MT), the main arsenic methylating enzyme. This was among the strongest selection signals (top 0.5% signals via locus-specific branch length and extended haplotype homozygosity tests) at a genome-wide level in the Bolivian study groups. We found a large haplotype block of 676 kb in the AS3MT region and identified candidate functional variants for further analysis. Moreover, our analyses revealed associations between AS3MT variants and the fraction of mono-methylated arsenic in urine and showed that the Bolivian study groups had the highest frequency of alleles associated with more efficient arsenic metabolism reported so far. Our data support the idea that arsenic exposure has been a driver for human adaptation to tolerate arsenic through more efficient arsenic detoxification in different Andean populations.

Arsenic exposure and biomarkers for oxidative stress and telomere length in indigenous populations in Bolivia.

BACKGROUND: Women living in the Bolivian Andes are environmentally exposed to arsenic, yet there is scarce information about arsenic-related effects in this region. Several biomarkers for telomere length and oxidative stress (mitochondrial DNA copy number, mtDNAcn; 8-Oxo-2'-deoxyguanosine, 8-oxo-dG; and 4-hydroxy nonenal mercapturic acid, 4-HNE-MA) have been previously linked to arsenic, and some of which are prospective biomarkers for cancer risk. OBJECTIVE AND HYPOTHESIS: To evaluate associations between arsenic exposure and telomere length, mtDNAcn, 8-oxo-dG, and 4-HNE-MA in Bolivians. Arsenic exposure was hypothesized to be positively associated with all four toxicity biomarkers, particularly in individuals with a less efficient arsenic metabolism. METHODS: The study encompassed 193 indigenous women. Arsenic exposure was assessed in urine as the sum of inorganic arsenic metabolite concentrations (U-As) measured by HPLC-HG-ICP-MS, and in whole blood as total arsenic (B-As) measured by ICP-MS. Efficiency of arsenic metabolism was evaluated by a polymorphism (rs3740393) in the main arsenic methylating gene AS3MT measured by TaqMan allelic discrimination, and by the relative fractions of urinary inorganic arsenic metabolites. Telomere length and mtDNAcn were determined in peripheral blood leukocytes by quantitative PCR, and urinary 8-oxo-dG and 4-HNE-MA by LC-MS/MS. RESULTS: U-As and B-As were associated with longer telomeres and higher mtDNAcn, particularly in women with a less efficient arsenic metabolism. Urinary 8-oxo-dG and 4-HNE-MA were positively associated with U-As, but only 4-HNE-MA was associated with B-As. Arsenic metabolism efficiency did not have a clear effect on the concentrations of either of these biomarkers. CONCLUSION: Bolivian women showed indications of arsenic toxicity, measured by four different biomarkers. Telomere length, mtDNAcn, and 4-HNE-MA were positively associated with both U-As and B-As. The association of arsenic exposure with telomere length and mtDNAcn was only present in Bolivian women with a less efficient metabolism. These findings call for additional efforts to evaluate and reduce arsenic exposure in Bolivia.

Thyroid Doses to French Polynesians Resulting from Atmospheric Nuclear Weapons Tests: Estimates Based on Radiation Measurements and Population Lifestyle Data.

Thyroid doses were estimated for the subjects of a population-based case-control study of thyroid cancer in a population exposed to fallout after atmospheric nuclear weapons tests conducted in French Polynesia between 1966 and 1974. Thyroid doses due to (1) intake of I and of short-lived radioiodine isotopes (I, I, I) and Te, (2) external irradiation from gamma-emitting radionuclides deposited on the ground, and (3) ingestion of long-lived Cs with foodstuffs were reconstructed for each study subject. The dosimetry model that had been used in 2008 in Phase I of the study was substantially improved with (1) results of radiation monitoring of the environment and foodstuffs, which became available in 2013 for public access, and (2) historical data on population lifestyle related to the period of the tests, which were collected in 2016-2017 using focus-group discussions and key informant interviews. The mean thyroid dose among the study subjects was found to be around 5 mGy while the highest dose was estimated to be around 36 mGy. Doses from I intake ranged up to 27 mGy, while those from intake of short-lived iodine isotopes (I, I, I) and Te ranged up to 14 mGy. Thyroid doses from external exposure ranged up to 6 mGy, and those from internal exposure due to Cs ingestion did not exceed 1 mGy. Intake of I was found to be the main pathway for thyroid exposure accounting for 72% of the total dose. Results of this study are being used to evaluate the risk of thyroid cancer among the subjects of the epidemiologic study of thyroid cancer among French Polynesians.

Arsenic Exposure and Cancer-Related Proteins in Urine of Indigenous Bolivian Women.

Indigenous people living in the Bolivian Andes are exposed through their drinking water to inorganic arsenic, a potent carcinogen. However, the health consequences of arsenic exposure in this region are unknown. The aim of this study was to evaluate associations between arsenic exposure and changes in cancer-related proteins in indigenous women (n = 176) from communities around the Andean Lake Poopó, Bolivia. Arsenic exposure was assessed in whole blood (B-As) and urine (as the sum of arsenic metabolites, U-As) by inductively coupled plasma-mass spectrometry (ICP-MS). Cancer-related proteins (N = 92) were measured in urine using the proximity extension assay. The median B-As concentration was 2.1 (range 0.60-9.1) ng/g, and U-As concentration was 67 (12-399) µg/L. Using linear regression models adjusted for age, urinary osmolality, and urinary leukocytes, we identified associations between B-As and four putative cancer-related proteins: FASLG, SEZ6L, LYPD3, and TFPI2. Increasing B-As concentrations were associated with lower protein expression of SEZ6L, LYPD3, and TFPI2, and with higher expression of FASLG in urine (no association was statistically significant after correcting for multiple comparisons). The associations were similar across groups with different arsenic metabolism efficiency, a susceptibility factor for arsenic toxicity. In conclusion, arsenic exposure in this region was associated with changes in the expression of some cancer-related proteins in urine. Future research is warranted to understand if these proteins could serve as valid biomarkers for arsenic-related toxicity.

Individual risk of post-ivermectin serious adverse events in subjects infected with Loa loa.

BACKGROUND: Implementation of onchocerciasis elimination programmes has been delayed in Central Africa because of the risk of ivermectin-related serious adverse events (SAEs) in individuals with high Loa loa microfilarial densities (MFD). We developed the first statistical models enabling prediction of SAE risk in individuals with a given MFD. METHODS: We used individual participant data from two trials conducted in loiasis-onchocerciasis co-endemic areas in Cameroon. among the 10 506 ivermectin-treated subjects included in the analysis, 38 (0·36%) developed an ivermectin-related SAE. To predict individual-level risk of SAE, we developed mixed multivariate logistic models including subjects' sex, age, pre-treatment L loa and Mansonella perstans MFDs, and study region. FINDINGS: The models predicted that regardless of sex, about 1% of people with 20 000 L loa microfilariae per millilitre of blood (mf/mL), 10% of people with 50 000 mf/mL and about one third of those with 100 000 mf/mL will develop an SAE. For a given MFD, males have a three-fold higher risk of developing an SAE than females. INTERPRETATION: By enabling the prediction of post-ivermectin SAE risk in communities with known distribution of L loa MFDs, our results can guide decisions on the choice of ivermectin-based treatment strategies. They also predict that 37 SAEs were prevented in 2015 by using a Test-and-Treat strategy in the Okola District of Cameroon. FUNDING: UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases; Institut de Recherche pour le Développement; Mectizan Donation Program; Bill & Melinda Gates Foundation.

Individuals living in an onchocerciasis focus and treated three-monthly with ivermectin develop fewer new onchocercal nodules than individuals treated annually.

BACKGROUND: Little information is available on the effect of ivermectin on the third- and fourth-stage larvae of Onchocerca volvulus. To assess a possible prophylactic effect of ivermectin on this parasite, we compared the effects of different ivermectin regimens on the acquisition of onchocercal nodules. METHODS: We analyzed data from a controlled randomized clinical trial of ivermectin conducted in the Mbam Valley (Cameroon) between 1994 and 1998 in a cohort of onchocerciasis infected individuals. The number of nodules that appeared between the start and the end of the clinical trial was analyzed, using ANOVA and multivariable Poisson regressions, between four treatment arms: 150 µg/kg annually, 800 µg/kg annually, 150 µg/kg 3-monthly, and 800 µg/kg 3-monthly. RESULTS: The mean number of nodules that appeared during the trial was reduced by 17.7% in subjects treated 3-monthly compared to those treated annually (regardless of the dose). Poisson regression model, adjusting on subject's age and weight, initial number of nodules and intensity of O. volvulus infection in his village of residence, confirmed that the incidence of new nodules was reduced in 3-monthly treatment arms compared to annually treatment arms, and that the dosage of ivermectin does not seem to influence this effect. Furthermore, the number of newly acquired nodules was positively associated with the initial number of nodules. Analysis of disappearance of nodules did not show any significant difference between the treatment groups. CONCLUSIONS: To our knowledge, these results suggest for the first time in humans, that ivermectin has a partial prophylactic effect on O. volvulus. Three-monthly treatment seems more effective than annual treatment to prevent the appearance of nodules.

Safety of high-dose ivermectin: a systematic review and meta-analysis.

BACKGROUND: Ivermectin is a key anthelmintic for the control of neglected tropical diseases. The main indications for population-level control with ivermectin through mass drug administration are onchocerciasis and lymphatic filariasis; however, there is interest in using higher, fixed-dose regimens for the control of scabies, soil-transmitted helminths and malaria. Safety data for these higher-dose regimens are needed. METHODS: A systematic literature review and meta-analysis on the safety and doses of ivermectin was conducted. Eligible studies reported patient-level data and, for the meta-analysis, clinical trials reporting data on doses ≥200 and ≥400 µg/kg were included. Incidence ratios were used to compare adverse events by severity and organ system affected. RESULTS: The systematic search identified six studies for inclusion, revealing no differences in the number of individuals experiencing adverse events. A descriptive analysis of these clinical trials for a variety of indications showed no difference in the severity of the adverse events between standard (up to 400 µg/kg) and higher doses of ivermectin. Organ system involvement only showed an increase in ocular events in the higher-dose group in one trial for the treatment of onchocerciasis, all of them transient and mild to moderate in intensity. CONCLUSIONS: Although within this review the safety of high-dose ivermectin appears to be comparable to standard doses, there are not enough data to support a recommendation for its use in higher-than-approved doses. Ocular adverse events, despite being transient, are of concern in onchocerciasis patients. These data can inform programme managers and guide operational research activities as new approaches for the use of ivermectin are evaluated.

Behavior and Food Consumption Pattern of the French Polynesian Population in the 1960s -1970s.

BACKGROUND: Reconstruction of radiation doses to the thyroid for a case-control study of thyroid cancer in French Polynesians exposed to radioactive fallout from atmospheric nuclear weapons tests during childhood and adolescence faced a major limitation on very little availability of information on lifestyle of French Polynesians in the 1960s-1970s. METHOD: We use the focus group discussion and key informant interview methodology to collect historical, for the 1960s-1970s, data on behavior and food consumption for French Polynesia population exposed to radioactive fallout from nuclear weapons tests conducted between 1966 and 1974. RESULTS: We obtained archipelago-specific data on food consumptions by children of different ages and by pregnant and lactating women during pregnancy and breastfeeding and behaviour, including time spent outdoors and type and construction materials of residences. CONCLUSIONS: This article presents the first detailed information on several key aspects of daily life on French Polynesian archipelagoes during the 1960s-1970s impacting radiation exposure. Important behavior and food consumptions data obtained in this study are being used to improve the radiation dose estimates and to update the risk analysis reported earlier by correcting biases from previous assumptions and by providing better estimates of the parameter values important to radiation dose assessment.

Effect of a Single Standard Dose (150-200 µg/kg) of Ivermectin on Loa loa Microfilaremia: Systematic Review and Meta-analysis.

BACKGROUND: In central Africa, millions of individuals infected with Loa loa have received the anthelminthic drug ivermectin (IVM) as part of mass drug administration (MDA) campaigns targeting onchocerciasis control or elimination. Nonetheless, the parasitological surveys that are occasionally conducted to evaluate the impact of IVM treatments on Onchocerca volvulus do not include an assessment of the extra benefits of those MDA campaigns on L. loa. METHODS: We conducted a systematic review of trials on the effect of a single standard (150-200 µg/kg) dose of IVM on L. loa microfilarial density (MFD). The dynamics of MFD over 365 days of treatment were described using multilevel regression and latent class modeling. RESULTS: IVM brings about a rapid, dramatic, and sustained decrease, with reduction rates of 60%, 75%, 85%, and 90% on day 1 (D1), D2, D7, and D365, respectively. At D365, no participants (0/238) with an initial MFD of <20 000 microfilariae (mf)/mL were at risk of postivermectin severe adverse events, and only 1/57 individuals with an initial MFD of ≥20 000 mf/mL presented with an MFD above this value. The main predictor of post-treatment MFD was the pretreatment value, but this post-treatment value varied little between D8 and D365 regardless of the pretreatment level. CONCLUSIONS: A single dose of IVM is very effective at substantially reducing L. loa MFD for at least a year, irrespective of the initial level of parasitemia. Individuals treated with IVM are probably not any more at risk of severe adverse events when retreated 1 year later.

Non-Essential Trace Elements Dietary Exposure in French Polynesia: Intake Assessment, Nail Bio Monitoring and Thyroid Cancer Risk

Background: In French Polynesia, thyroid cancer mortality and incidence is reported to be the highest in the world. Excessive levels of non-essential trace elements (nETE) in the body are associated with several types of cancer. Objective: The present study aims to provide quantitative information on food contamination by mercury (Hg), lead (Pb), arsenic (As) and cadmium (Cd) in French Polynesia and its potential correlation with measurements performed in fingernails of Polynesians, and then to investigate the potential association between these nETE and different thyroid cancer risks. Methods: The study population included 229 interviewed cases and 373 interviewed controls We performed a descriptive analysis of Polynesian food and examined the association between thyroid cancer risk and daily intake levels of nETE and with fingernail nETE levels. Results: Hg contamination was mainly present in sea products, Pb contamination was present in almost all samples, Cd was detectable in starchy food and As was detectable in all sea products. No patient exceeded dietary contamination WHO limits for Pb, 2 participants exceeded it for Hg and 3 individuals (0.5%) for cadmium. In fingernail clippings, the most detectable pollutant was Pb (553 participants), then Hg (543 participants) then Cd (only in 130 participants). Thyroid cancer risk was increased more than 4 times by Pb daily intake in patients with a history of cancer in first-degree relatives than in ones without (p for interaction =0.01), and 2 times more in women with more than 3 pregnancies than in those with none or less (p for interaction =0.005); it was also increased following As intake by more than 30% in patients with a history of cancer in first-degree relatives than in ones without (p for interaction =0.05). Conclusion: Locally produced foods are not a source of nETE exposure in French Polynesia. Dieatry nETE exposure and fingernail nETE concentration are not associated to differentiated thyroid cancer risk. No correlation found between nETE dietary exposure and fingernail nETE concentration.

Elevated arsenic exposure and efficient arsenic metabolism in indigenous women around Lake Poopó, Bolivia.

Elevated concentrations of inorganic arsenic, one of the most potent environmental toxicants and carcinogens, have been detected in well water around Lake Poopó, Bolivia. This study aimed to assess human exposure to arsenic in villages around Lake Poopó, and also to elucidate whether the metabolism and detoxification of arsenic in this population is as efficient as previously indicated in other Andean areas. We recruited 201 women from 10 villages around Lake Poopó. Arsenic exposure was determined as the sum concentration of arsenic metabolites (inorganic arsenic; monomethylarsonic acid, MMA; and dimethylarsinic acid, DMA) in urine (U-As), measured by HPLC-HG-ICP-MS. Efficiency of arsenic metabolism was assessed by the relative fractions of the urinary metabolites. The women had a wide variation in U-As (range 12-407 µg/L, median 65 µg/L) and a markedly efficient metabolism of arsenic with low %MMA (median 7.7%, range: 2.2-18%) and high %DMA (80%, range: 54-91%) in urine. In multivariable-adjusted linear regression models, ethnicity (Aymara-Quechua vs. Uru), body weight, fish consumption and tobacco smoking were associated with urinary arsenic metabolite fractions. On average, the Uru women had 2.5 lower % (percentage unit) iAs, 2.2 lower %MMA and 4.7 higher %DMA compared with the Aymara-Quechua women. Our study identified several factors that may predict these women's arsenic methylation capacity, particularly ethnicity. Further studies should focus on mechanisms underlying these differences in arsenic metabolism efficiency, and its importance for the risk of arsenic-related health effects.

Herbal Medicine Practices of Patients With Liver Cancer in Peru: A Comprehensive Study Toward Integrative Cancer Management.

RATIONALE: The highest burden of liver cancer occurs in developing countries, where the use of herbal medicine (HM) is still widespread. Despite this trend, few studies have been conducted to report HM practices of patients with a hepatic tumor in the developing world. Hence, this study aimed to document the use of HM among patients with liver cancer in Peru. STUDY DESIGN AND METHODS: A comparative behavioral epidemiological survey was conducted among liver cancer patients attending the National Cancer Institute of Peru. Information was obtained by direct interviews based on a semistructured questionnaire. The use of HM in Peruvian liver cancer patients was reported, first, regarding general consumption prior to the onset of disease, and second, after the appearance of symptoms that patients would relate to their tumor. In parallel, general consumption of HM in noncancerous people was assessed as a comparative figure. A correspondence analysis was performed to reveal potential associations between the symptoms of cancer and the specific use of HM. RESULTS: Eighty-eight patients and 117 noncancerous individuals participated in the survey. Overall, 68.3% of the people interviewed claimed to use HM on a regular basis for general health preservation. Furthermore, 56.8% of the patients turned to plants first to treat the disorders for which they later came to the cancer care center. When compared with the number of plant species used routinely (n = 78), a selection of plants was made by patients in response to the symptoms of cancer (n = 46). At least 2 plant species, Aloe vera and Morinda citrifolia, were significantly associated with the treatment of liver cancer-related symptoms in the patient group. CONCLUSIONS: The present study is the first survey on the HM practices of patients with liver cancer in Latin America and, more broadly, in the developing world. Our findings confirm that HM remains one of the principal primary health care resources in Peru, even for a severe disease like liver cancer. These traditional, complementary and alternative medicine practices should be taken into consideration in Peruvian health programs aiming to educate the population in cancer prevention and treatment, as well as integrative cancer management.

Macrofilaricidal Efficacy of Repeated Doses of Ivermectin for the Treatment of River Blindness.

BACKGROUND: Mass drug administration (MDA) with ivermectin is the cornerstone of efforts to eliminate human onchocerciasis by 2020 or 2025. The feasibility of elimination crucially depends on the effects of multiple ivermectin doses on Onchocerca volvulus. A single ivermectin (standard) dose clears the skin-dwelling microfilarial progeny of adult worms (macrofilariae) and temporarily impedes the release of such progeny by female macrofilariae, but a macrofilaricidal effect has been deemed minimal. Multiple doses of ivermectin may cumulatively and permanently reduce the fertility and shorten the lifespan of adult females. However, rigorous quantification of these effects necessitates interrogating longitudinal data on macrofilariae with suitably powerful analytical techniques. METHODS: Using a novel mathematical modeling approach, we analyzed, at an individual participant level, longitudinal data on viability and fertility of female worms from the single most comprehensive multiple-dose clinical trial of ivermectin, comparing 3-monthly with annual treatments administered for 3 years in Cameroon. RESULTS: Multiple doses of ivermectin have a partial macrofilaricidal and a modest permanent sterilizing effect after 4 or more consecutive treatments, even at routine MDA doses (150 µg/kg) and frequencies (annual). The life expectancy of adult O. volvulus is reduced by approximately 50% and 70% after 3 years of annual or 3-monthly (quarterly) exposures to ivermectin. CONCLUSIONS: Our quantification of macrofilaricidal and sterilizing effects of ivermectin should be incorporated into transmission models to inform onchocerciasis elimination efforts in Africa and residual foci in Latin America. It also provides a framework to assess macrofilaricidal candidate drugs currently under development.

Metal concentration and bioaccessibility in different particle sizes of dust and aerosols to refine metal exposure assessment.

Refined exposure assessments were realized for children, 7-9yrs, in the mining/smelting city of Oruro, Bolivia. Aerosols (PM>2.5, PM1-2.5, PM0.4-1 and PM0.5) and dust (separated in different particle size fractions: 2000-200µm, 200-50µm, 50-20µm, 20-2µm and <2µm) were sampled on football fields highly frequented by children in both the mining and smelting areas. Trace element concentrations (Ag, As, Cd, Cu, Pb, Sb, Sn and Zn) in each size fraction of dust and aerosols, lung bioaccessibility of metals in aerosols, and gastric bioaccessibility of metals in dust were measured. Exposure was assessed considering actual external exposure (i.e. exposure pathways: metals inhaled and ingested) and simulated internal exposure (i.e., complex estimation using gastric and lung bioaccessibility, deposition and clearance of particles in lungs). Significant differences between external and simulated internal exposure were attributed to dissemblances in gastric and lung bioaccessibilities, as well as metal distribution within particle size range, revealing the importance of both parameters in exposure assessment.

Toxic trace elements in maternal and cord blood and social determinants in a Bolivian mining city.

This study assessed lead, arsenic, and antimony in maternal and cord blood, and associations between maternal concentrations and social determinants in the Bolivian mining city of Oruro using the baseline assessment of the ToxBol/Mine-Niño birth cohort. We recruited 467 pregnant women, collecting venous blood and sociodemographic information as well as placental cord blood at birth. Metallic/semimetallic trace elements were measured using inductively coupled plasma mass spectrometry. Lead medians in maternal and cord blood were significantly correlated (Spearman coefficient = 0.59; p < 0.001; 19.35 and 13.50 µg/L, respectively). Arsenic concentrations were above detection limit (3.30 µg/L) in 17.9% of maternal and 34.6% of cord blood samples. They were not associated (Fischer's p = 0.72). Antimony medians in maternal and cord blood were weakly correlated (Spearman coefficient = 0.15; p < 0.03; 9.00 and 8.62 µg/L, respectively). Higher concentrations of toxic elements in maternal blood were associated with maternal smoking, low educational level, and partner involved in mining.

Indoor metallic pollution and children exposure in a mining city.

Mining industries are known for causing strong environmental contamination. In most developing countries, the management of mining wastes is not adequate, usually contaminating soil, water and air. This situation is a source of concern for human settlements located near mining centers, especially for vulnerable populations such as children. The aim of this study was to assess the correlations of the metallic concentrations between household dust and children hair, comparing these associations in two different contamination contexts: a mining district and a suburban non-mining area. We collected 113 hair samples from children between 7 and 12 years of age in elementary schools in the mining city of Oruro, Bolivia. We collected 97 indoor dust samples from their households, as well as information about the children's behavior. Analyses of hair and dust samples were conducted to measure As, Cd, Pb, Sb, Sn, Cu and Zn contents. In the mining district, there were significant correlations between non-essential metallic elements (As, Cd, Pb, Sb and Sn) in dust and hair, but not for essential elements (Cu and Zn), which remained after adjusting for children habits. Children who played with dirt had higher dust-hair correlations for Pb, Sb, and Cu (P=0.006; 0.022 and 0.001 respectively) and children who put hands or toys in their mouths had higher dust-hair correlations of Cd (P=0.011). On the contrary, in the suburban area, no significant correlations were found between metallic elements in dust and children hair and neither children behavior nor gender modified this lack of associations. Our results suggest that, in a context of high metallic contamination, indoor dust becomes an important exposure pathway for children, modulated by their playing behavior.