Pantelis Charisiadis

Biomonitoring of human exposures to chlorinated derivatives and structural analogs of bisphenol A

The high reactivity of bisphenol A (BPA) with disinfectant chlorine is evident in the instantaneous formation of chlorinated BPA derivatives (ClxBPA) in various environmental media that show increased estrogen-activity when compared with that of BPA. The documented health risks associated with BPA exposures have led to the gradual market entry of BPA structural analogs, such as bisphenol S (BPS), bisphenol F (BPF), bisphenol B (BPB), etc. A suite of exposure sources to ClxBPA and BPA analogs in the domestic environment is anticipated to drive the nature and range of halogenated BPA derivatives that can form when residual BPA comes in contact with disinfectant in tap water and/or consumer products. The primary objective of this review was to survey all available studies reporting biomonitoring protocols of ClxBPA and structural BPA analogs (BPS, BPF, BPB, etc.) in human matrices. Focus was paid on describing the analytical methodologies practiced for the analysis of ClxBPA and BPA analogs using hyphenated chromatography and mass spectrometry techniques, because current methodologies for human matrices are complex. During the last decade, an increasing number of ecotoxicological, cell-culture and animal-based and human studies dealing with ClxBPA exposure sources and routes of exposure, metabolism and toxicity have been published. Up to date findings indicated the association of ClxBPA with metabolic conditions, such as obesity, lipid accumulation, and type 2 diabetes mellitus, particularly in in-vitro and in-vivo studies. We critically discuss the limitations, research needs and future opportunities linked with the inclusion of ClxBPA and BPA analogs into exposure assessment protocols of relevant epidemiological studies.

Household cleaning activities as noningestion exposure determinants of urinary trihalomethanes.

Previous epidemiological studies linking drinking water total trihalomethanes (THM) with pregnancy disorders or bladder cancer have not accounted for specific household cleaning activities that could enhance THM exposures. We examined the relation between household cleaning activities (washing dishes/clothes, mopping, toilet cleaning, and washing windows/surfaces) and urinary THM concentrations accounting for water sources, uses, and demographics. A cross-sectional study (n = 326) was conducted during the summer in Nicosia, Cyprus, linking household addresses to the geocoded public water pipe network, individual household tap water, and urinary THM measurements. Household tap water THM concentrations ranged between 3-129 μg L(-1), while the median (Q1, Q3) creatinine-adjusted urinary THM concentration in females (669 ng g(-1) (353, 1377)) was significantly (p < 0.001) higher than that in males (399 ng g(-1), (256, 681)). Exposure assessment, based on THM exposure equivalency units, showed that hand dishwashing, mopping, and toilet cleaning significantly (p < 0.001) increased urinary THM levels. The effect of dishwashing by females ≥36 y of age remained significant, even after adjusting for potential confounders. No significant (p > 0.05) association was observed between ingestion-based THM exposure equivalency units and urinary THM. Noningestion routes of THM exposures during performance of routine household cleaning activities were shown for the first time to exert a major influence on urinary THM levels. It is warranted that future pregnancy-birth cohorts include monitoring of noningestion household THM exposures in their study design.

Human Exposures to Bisphenol A, Bisphenol F and Chlorinated Bisphenol A Derivatives and Thyroid Function

Although the increasing prevalence of thyroid nodular disease (TND) has been partially attributed to the more frequent usage of improved diagnostics, environmental factors, such as exposures to thyroid-disrupting chemicals may contribute to TND and altered thyroid function. We investigated the association between exposures to bisphenol A (BPA), its chlorinated derivatives (ClxBPA), and bisphenol F (BPF) with TND and thyroid measures in adult women. A case-control study in Cyprus and Romania (n = 212) was conducted, where cases were those with thyroid nodules (diameter >3mm), and controls without nodules. Serum TSH and free thyroxine and urinary levels of BPA, BPF and ClxBPA were measured using immunoassays and tandem mass spectrometry, respectively. The association between exposures to BPA compounds and TND, adjusting for age, BMI, thyroid hormones and urinary iodine was assessed using logistic regression. Linear regression was used to explore associations between urinary BPA, BPF and ClxBPA and serum thyroid hormones. With the exception of a chlorinated BPA compound (30%), the rest of bisphenols were quantified in 100% of urine samples. A positive and significant (p<0.05) association was observed between urinary BPA and serum TSH that remained after adjusting for urinary creatinine, age, BMI, study site and disease status; there was no significant association between BPF or ClxBPA with TSH. None of the BPA compounds were associated with higher odds of TND. Our study found associations of urinary BPA with TSH but not with BPF or ClxBPA. A larger study would be justified.

Influence of household cleaning practices on the magnitude and variability of urinary monochlorinated bisphenol A

Low-dose health effects of BPA have not been adequately explored in the presence of BPA metabolites of chlorinated structure that may exert larger estrogenic effects than those of their parent compound. We hypothesized that chlorine-containing cleaning products used in household cleaning activities could modify the magnitude of total urinary BPA concentration measurements via the production of chlorinated BPA (ClBPA) derivatives. Our objective was to investigate the influence of typical household cleaning activities (dishwashing, toilet cleaning, mopping, laundry, etc.) on the magnitude and variability of urinary total BPA and mono-ClBPA levels in the general adult population. A cross-sectional study (n=224) included an adult (≥18 years) pool of participants from the general population of Nicosia, Cyprus. First morning urine voids were collected, and administered questionnaires included items about household cleaning habits, demographics, drinking water consumption rates and water source/usage patterns. Urinary concentrations of total BPA (range: 0.2-82 μg L(-1)), mono-ClBPA (16-340 ng L(-1)), and total trihalomethanes (0.1-5.0 μg L(-1)) were measured using gas chromatography coupled with triple quadrupole mass spectrometry and large volume injection. Linear multiple regression analysis revealed that dishwashing along with age and gender (females) were able to predict urinary mono-ClBPA levels (ng g(-1)), even after adjusting for covariates; this was not the case for urinary total BPA levels (ng g(-1)). Significant (p<0.001) association was observed between urinary mono-ClBPA and THM levels, underlying the important role of disinfectant (chlorine) in promoting formation of both ClBPA and THM. Urinary mono-ClBPA levels were measured for the first time using an appreciable sample size, highlighting the co-occurring patterns of both total BPA and mono-ClBPA. Epidemiological studies and probabilistic BPA risk assessment exercises should consider assessing daily intake estimates for chlorinated BPA compounds, as well.

Occurrence and variability of iodinated trihalomethanes concentrations within two drinking-water distribution networks

Non-iodo-containing trihalomethanes (TTHM) are frequently detected in chlorinated tap water and currently regulated against their carcinogenic potential. Iodinated THM (ITHM) may also form in disinfected with chlorine waters that are high in iodine content, but little is known about their magnitude and variability within the drinking-water pipe distribution network of urban areas. The main objective of this study was to determine the magnitude and variability of ITHM and TTHM levels and their corresponding daily intake estimates within the drinking water distribution systems of Limassol and Nicosia cities of Cyprus, using tap samples collected from individual households (n=37). In Limassol, mean household tap water ITHM and TTHM levels was 0.58 and 38 μg L(-1), respectively. Dichloroiodomethane (DCIM) was the dominant species of the two measured ITHM compounds accounting for 77% of total ITHM and in the range of 0.032 and 1.65 μg L(-1). The range of DCIM concentrations in Nicosia tap water samples was narrower (0.032 - 0.848 μg L(-1)). Mean total iodine concentration in tap water samples from the seaside city of Limassol was 15 μg L(-1) and approximately twice to those observed in samples from the mainland Nicosia city. However, iodine concentrations did not correlate with the ITHM levels. The calculated chronic daily intake rates of ITHM were low when compared with those of TTHM, but because of their widespread occurrence in tap water and their enhanced mammalian cell toxicity, additional research is warranted to assess the magnitude and variability of human ITHM exposures.

Spatial and seasonal variability of tap water disinfection by-products within distribution pipe networks

Gradually-changing shocks associated with potable water quality deficiencies are anticipated for urban drinking-water distribution systems (UDWDS). The impact of structural UDWDS features such as, the number of pipe leaking incidences on the formation of water trihalomethanes (THM) at the geocoded household level has never been studied before. The objectives were to: (i) characterize the distribution of water THM concentrations in households from two district-metered areas (DMAs) with contrasting UDWDS characteristics sampled in two seasons (summer and winter), and (ii) assess the within- and between-household, spatial variability of water THM accounting for UDWDS characteristics (household distance from chlorination tank and service pipe leaking incidences). A total of 383 tap water samples were collected from 193 households located in two DMAs within the UDWDS of Nicosia city, Cyprus, and analyzed for the four THM species. The higher intraclass correlation coefficient (ICC) values for water tribromomethane (TBM) (0.75) followed by trichloromethane (0.42) suggested that the two DMAs differed with respect to these analytes. On the other hand, the low ICC values for total THM levels between the two DMAs suggested a large variance between households. The effect of households nested under each DMA remained significant (p<0.05) for TBM (not for the rest of the THM species) in the multivariate mixed-effect models, even after inclusion of pipe network characteristics. Our results could find use by water utilities in overcoming techno-economic difficulties associated with the large spatiotemporal variability of THM, while accounting for the influence of UDWDS features at points of water use.

Preliminary evidence of the association between monochlorinated bisphenol A exposure and type II diabetes mellitus: A pilot study

Evidence for the association of bisphenol A (BPA) with type II diabetes mellitus (T2DM) has been inconsistent in human studies. In-vitro and animal studies indicate that chlorinated BPA derivatives aggravate BPA health effects via higher estrogenic activity and alteration of membrane-initiating signaling pathways. We evaluated the association between urinary monochlorinated BPA (mono-ClBPA) concentrations and the incidence of T2DM. In our cross-sectional study, we identified 20 adult participants (≥18 yr) who reported having T2DM (doctor-diagnosed) and 131 adults with normal health. First morning void urine samples were analyzed for total BPA and mono-ClBPA. Detection limits of the analytical method were 95 ng L−1 for BPA and 32 ng L−1 for mono-ClBPA. Multivariable logistic regression analyses and additive Bayesian network modeling were performed. After adjusting for age, gender, BMI, urinary total BPA and other confounders, the odds of having T2DM was 3.29 times higher (95% confidence interval, CI: 1.10, 11.4; P < 0.05) per unit increase in log-transformed and creatinine-adjusted urinary mono-ClBPA levels (n = 151); this relation did not hold for total BPA. The globally optimum Bayesian model corroborated the results of the logistic regression by expressing mono-ClBPA in the pathway of T2DM, and not for total BPA. An age-matched sensitivity analysis confirmed the increase in OR of T2DM by 3.04 times (95% CI: 1.10, 11.0; P < 0.05) per unit increase in log-transformed and creatinine-adjusted urinary mono-ClBPA concentration (n = 68). The urinary monochlorinated BPA derivative was significantly associated with T2DM, whereas the parent compound (total BPA) was not. Caution should be applied in interpreting these findings, as this is the first study to report this association and the sample size of participants with T2DM is small. Additional research with a larger sample size coupled with relevant toxicological studies is warranted.

Evidence of arsenic release promoted by disinfection by-products within drinking-water distribution systems

Changes in disinfectant type could trigger a cascade of reactions releasing pipe-anchored metals/metalloids into finished water. However, the effect of pre-formed disinfection by-products on the release of sorbed contaminants (arsenic-As in particular) from drinking water distribution system pipe scales remains unexplored. A bench-scale study using a factorial experimental design was performed to evaluate the independent and interaction effects of trihalomethanes (TTHM) and haloacetic acids (HAA) on arsenic (As) release from either scales-only or scale-biofilm conglomerates (SBC) both anchored on asbestos/cement pipe coupons. A model biofilm (Pseudomonas aeruginosa) was allowed to grow on select pipe coupons prior experimentation. Either TTHM or HAA individual dosing did not promote As release from either scales only or SBC, detecting <6 μg AsL(-1) in finished water. In the case of scales-only coupons, the combination of the highest spike level of TTHM and HAA significantly (p<0.001) increased dissolved and total As concentrations to levels up to 16 and 95 μg L(-1), respectively. Similar treatments in the presence of biofilm (SBC) resulted in significant (p<0.001) increase in dissolved and total recoverable As up to 20 and 47 μg L(-1), respectively, exceeding the regulatory As limit. Whether or not, our laboratory-based results truly represent mechanisms operating in disinfected finished water in pipe networks remains to be investigated in the field.

Obesity-mediated association between exposure to brominated trihalomethanes and type II diabetes mellitus: an exploratory analysis.

With the exception of chloroform, the rest of trihalomethanes (THM), the so-called brominated THM (Br-THM) are composed of bromine-substituted molecules with increased lipophilicity and potency to biological tissues. The THM are formed within disinfected tap water and their health effects, under research, range from cancer to adverse reproductive outcomes. However, the association between human exposures to Br-THM and the risk of developing type II diabetes mellitus (T2DM) and metabolic co-morbidities, such as obesity and non-alcoholic steatohepatitis has never been previously explored. The objective of this exploratory analysis was to address obesity-mediated associations between urinary concentrations of brominated THM and incidences of T2DM in a Cypriot adult population (n=326). First morning urine voids were collected once during summer and another time during winter while a detailed questionnaire was administered to participants. Creatinine-adjusted urinary Br-THM analyte concentrations were significantly (p<0.05) higher in T2DM cases when compared with those in healthy individuals. Multivariate logistic regression models adjusted for potential confounders showed that participants with ≥30 kg m(-2) BMI were at a higher T2DM risk (OR=8.42, 95% CI: 1.97, 45.5; p<0.01) when compared with that of normal weight participants (<25 kg m(-2)). About 4 times higher risk for developing T2DM was observed for individuals in the upper tertile of urinary Br-THM levels (OR=3.99, 95% CI: 1.07, 19.7; p<0.05) when compared with the lower tertile participants. Among the participants with BMI≥25 kg m(-2), urinary Br-THM levels were significantly (p<0.001) higher in diabetics than in healthy individuals. Ingestion and non-ingestion exposures to Br-THM deserve careful consideration in relevant epidemiological studies, as a possible environmental risk factor of T2DM.

Spatial and seasonal variability of urinary trihalomethanes concentrations in urban settings.

A complex network of sources and routes of exposure to disinfection by-products (DBP), such as trihalomethanes (THM) has been driving the wide variability of daily THM intake estimates in environmental epidemiological studies. We hypothesized that the spatiotemporal variability of THM exposures could be differentially expressed with their urinary levels among residents whose households are geographically clustered in district-metered areas (DMA) receiving the same tap water. Each DMA holds unique drinking-water pipe network characteristics, such as pipe length, number of pipe leaking incidences, number of water meters by district, average minimum night flow and average daily demand. The present study assessed the spatial and seasonal variability in urinary THM levels among residents (n=310) of geocoded households belonging to two urban DMA of Nicosia, Cyprus, with contrasting water network properties. First morning urine voids were collected once in summer and then in winter. Results showed that the mean sum of the four urinary THM analytes (TTHM) was significantly higher during summer for residents of both areas. Linear mixed effects models adjusted for age, season and gender, illustrated spatially-resolved differences in creatinine-adjusted urinary chloroform and TTHM levels between the two studied areas, corroborated by differences observed in their pipe network characteristics. Additional research is warranted to shed light on the contribution of spatially-resolved and geographically-clustered environmental exposures coupled with internal biomarker of exposure measurements towards better understanding of health disparities within urban centers.