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Phthalates are diesters of phthalic acid that are widely used in industry and personal care products resulting in exposure via ingestion, inhalation and dermal routes. There is an interest in the safety evaluation of phthalate exposure because these compounds are ubiquitous environmental contaminants with endocrine-disrupting properties, suspected to interfere with developmental androgen action, possibly leading to adverse effects on reproductive function. Toxicological properties of phthalates, the presence of phthalates in polyethylene terephthalate (PET) bottles as impurities, the high and regular consumption of bottled water, and the uncertainty about the impact of storage conditions of PET bottled water on migration of phthalates into the water, initiated the interest in their presence in bottled water and the accompanying risk assessment. In this study, common Iranian brands of bottled water were screened for phthalates. The effect of storage temperature on selected target chemical concentrations was investigated. A toxicological risk assessment was conducted to determine the potential health risks associated with the consumption of the bottled water. Along with indirect exposure assessment, a human biomonitoring approach was applied to facilitate better human exposure assessment of individual phthalates and their mixtures providing important information for identifying exposure sources and the contribution of intake from bottled water to the total daily intake.
Chapter 1 of the thesis presents an introduction to the topic, the toxicological properties of phthalates, risk assessment strategies and the regulatory status of phthalates. Chapter 2 of the thesis describes the development of a method to extract phthalates from bottled water by applying surface-functionalized magnetic particles (MPs) as the adsorbent used in Magnetic Solid-Phase Extraction (MSPE). Based on the results obtained, it was concluded that the MSPE-GC-MS method developed provides a new method for the determination of phthalates in water samples.
To extend the work to real samples chapter 3 presents the occurrence and concentrations of common phthalates (dibutyl phthalate (DBP), butyl benzyl phthalate (BBP), and diethylhexyl phthalate (DEHP) ) in PET bottled water locally produced in the Iranian market and stored under various common storage conditions. According to the results obtained, an increase in temperature and/or in the duration of storage increases phthalate migration. The highest concentrations of all phthalates were observed when bottled water samples were kept at 40 °C for 45 days. DEHP in bottled water was the most abundant phthalate under all storage conditions, although the observed level of DEHP in the worst-case scenario (40 °C for 45 days) was still much lower than the DEHP maximum concentration limit (MCL) in bottled water (MCL= 6 µg/L) set by the U.S. Food and Drug Administration (U.S. FDA). When comparing the concentrations of DBP, BBP and DEHP with initial levels in the bottled water, the results demonstrate that the release of phthalates was not substantial under all storage conditions, and especially minimal at low temperatures (<25 °C) and under freezing conditions. Based on the measured concentrations of phthalates, an indirect exposure assessment through PET bottled water consumption was performed for children in Iran. The risk assessment indicated that non-carcinogenic risks for DEHP, DBP, and BBP were low, and that the carcinogenic risks for DEHP were negligible.
In chapter 4, concentrations of diethyl phthalate (DEP) were measured in bottled water kept under various storage conditions, similar as those used in chapter 3 for DEHP, DBP and BBP, and the resulting risks of consumption of this water for children but also for other age groups were evaluated. The results indicate that storage duration and storage temperature also influence the release of DEP from PET bottles into water. In comparison to the initial level of DEP in bottled water samples, the migration of DEP appeared not considerable under most storage conditions, especially at low temperatures (<25 °C) and freezing conditions. The level of exposure to DEP (expressed as mg/kg body weight/day) via consumption of bottled water in different age groups based on the worst-case scenario exposure assessment was as follows: pre-school children > children > lactating women > teenagers > adults > pregnant women. However, for all age groups, none of the individuals exceeds existing intake limit values for DEP.
Due to the anti-androgenic activity of some phthalates, in chapter 5 the cumulative health risks in pregnant and lactating women posed by combined exposure to BBP, DBP, and DEHP via consumption of bottled water was estimated. To this end, hazard quotient (HQ) values, representing the margin between health based guidance values (EPA RfD values) and estimated exposures, and hazard index (HI) values, representing the sum of HQ values of individual phthalates, were determined. The results of the study showed that the HQ values for individual phthalate intake via bottled water consumption in pregnant and lactating women were much lower than 1, and cumulative risk assessment for combined phthalate exposure demonstrated that the HIs for anti-androgenic effects were also lower than 1 which implies that adverse effects are unlikely to occur.
In chapter 6 of the thesis a systematic review method was used to investigate whether the phthalate exposure would be a factor contributing to the development of autism spectrum disorders (ASD). The results of this systematic review revealed that only a limited number of studies has addressed phthalates in relation to autism. A total of five studies met the inclusion criteria and were included in the review. Of the 5 studies, two studies were cohort studies both from the U.S.A. and three were case-control studies conducted in the U.S.A., Italy and Turkey. Because of the heterogeneity in the type of included studies, different methods of assessing exposure to phthalates and the use of different statistics for summarizing the results, a meta-analysis could not be performed to combine the results of included studies. The review showed equivocal evidence for a possible connection between exposure to phthalates and ASD. Further comprehensive research is needed with appropriate attention to exposure assessment and relevant pre and post-natal confounders.
In the next step we set our goal to get better insight in the total phthalate exposure of Iranian children, and to assess the proportion of phthalate intake from bottled water to the total daily intake. This was done using biomonitoring based exposure assessment. Chapter 7 of the thesis shows the data on the levels of phthalate metabolites in the spot urine samples of children and adolescents. We applied a calculation model based on the creatinine-adjusted urinary metabolite concentrations to obtain the EDIs for DEHP, DBP and BBP. The EDI values thus obtained were compared to available health-based guidance values (RfD and TDI values based on anti-androgenic effects). Assuming additive effects, the cumulative risk for combined exposure were estimated for three phthalates based on anti-androgenicity as the critical effect. The results from the risk assessment suggest that Iranian children and adolescents are exposed to low levels of a mixture of these phthalates. Risk assessment indicates that not only the exposure to the single phthalates, but also the combined exposure would not raise a safety concern. However, people typically come into contact with several chemicals with anti-androgenic properties in addition to the investigated phthalates in this study, which may also contribute to combined anti-androgenic effects. This indicates that a risk assessment of combined exposure including other anti-androgenic chemicals would be required to determine whether combined exposure to anti-androgenic chemicals is below acceptable levels. Comparison of the exposure values obtained to those obtained based on indirect estimates in earlier chapters of the thesis, revealed that bottled water provides only a limited contribution to total daily phthalates exposure in Iran.
Chapter 8 presents a discussion of the results obtained and also presents some perspectives for future research and risk management of exposure to phthalates in Iran.
|Qualification||Doctor of Philosophy|
|Award date||16 Nov 2018|
|Place of Publication||Wageningen|
|Publication status||Published - 2018|