Phthalate monoeste

Hauser, R., Meeker, J.D., and Singh, N.R et al. (2007). DNA damage in human sperm is related to urinary levels of phthalate monoester and oxidative metabolites. Human Reproduction 22, 688-695. 

Koch HM, Rossbach B, Drexler H, Angerer J (2003) Internal exposure of the general population to DEHP and other phthalates - determination of secondary and primary phthalate monoester metabolites in urine. Environ Res 93 177-185... 

Animal studies have shown that di- -octylphthalate metabolites (primarily the corresponding phthalate monoesters) can be measured in the urine of rats orally exposed to di- -octy lphthalate. Therefore, these phthalate monoesters could be useful biomarkers of exposure. There are no other known biomarkers of exposure to di-ra-octylphthalate. 

Exposure. Methods for Determining Parent Compounds and Degradation Products in Environmental Media.Methods are available for measuring di-tt-octylphthalate and/or its metabolites (primarily the corresponding phthalate monoesters) in urine, blood, and tissues (Albro and Moore 1974 Lanina et al. 

Klaunig JE, Ruch RJ, DeAngelo AB, et al. 1988. Inhibition of mouse hepatocyte intercellular communication by phthalate monoesters. Cancer Lett 43 65-71. 

Parent phthalate Monoester metabolite Secondary oxidized metabolite... 

Hauser R, Meeker JD, Duty S, Silva MJ, Calafat AM (2006) Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiology 17 682-691... 

Baker, T.K., Kalimi, G.H., Lington, A.W., Isenberg, J.S., Klaunig, J.E. Nikiforov, A.I. (1996) Gap junctional intercellular communication (GJIC) studies on 5 phthalate monoesters in hepatocytes of four species implications for cancer risk assessment (Abstract). Toxicologist, 30, 208... 

M). Large rate enhancements occur for base hydrolysis of the complexes, ranging from 104 with Ni° to 106 with Cu11. A pH-independent reaction occurs with the phthalate monoester due to intramolecular nucleophilic attack by the neighbouring carboxylate group leading to rate enhancements of 102-104. Metal ion-promoted water hydrolysis was also observed with these esters. 

A Total Diet Study carried out in the UK in 1993 detected low levels of a range of individual phthalates in composite samples of carcass meat, poultry, eggs and milk.69 Only low levels (generally < 0.07 mg/kg) were found. Total phthalate was determined (by conversion of any phthalate in the samples to dimethyl phthalate) in carcass meat, eggs, meat products, offals, poultry, fish, fats and oils, milk and milk products. Each food group was found to contain total phthalate in a range between 0.5 and 8.8 mg/kg. This difference may be due to the presence of phthalate monoester metabolites, which would be included in the analytes. The dietary exposures of even 97.5th percentile consumers were estimated to be within the TDIs for DEHP, BBP and DBP. 

Application of LC-MS/MS techniques to the analysis of phthalate ester metabolites in urine have also been developed. For example, Blount et al. (2000b) have developed an assay to quantify the monoester metabolites (including MEHP) of eight phthalate diesters in urine, utilizing HPLC coupled with atmospheric pressure chemical ionization and tandem mass spectrometric (APCI-MS/MS) detection techniques. Urine samples were treated with -glucuronidase to release the free phthalate monoesters followed by a two-step solid phase extraction procedure. After evaporative concentration of the eluant, the analytes in the purified samples are further separated on a phenyl reverse phase HPLC column and quantified by APCI-MS/MS, following careful optizimation of the APCI-MS/MS instrument. The limits of detection for MEHP were determined to be 1.2 ng/ml urine with recovery efficiencies of between 78 and 91%. 

B. G. Lake, T. J. B. Gray, D. F. V. Lewis, J. A. Beamand, K. D. Hodder, R. Purchase, and S. D. Gangolli, Toxicol. Ind. Health, 3, 165 (1987). Structure-Activity Relationships for Induction of Peroxisomal Enzyme Activities by Phthalate Monoesters in Primary Rat Hepatocyte Cultures. 

Hurst CH, Waxman DJ. Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicol Sci 2003 74 297-308. 

Bility, M. T., Thointson, J. T, McKee, R. H., David, R. M., Butala, J. H., Vanden Heuvel, J. R, and Peters, J. M. (2004). Activation of mouse and human peroxisome prolifaratOT-activated recepta-s (PPARs) by phthalate monoesters. Toxicol Sci 82, 170-182. 

The extent to which intramolecular nucleophilic catalysis of the type depicted in mechanism I is important is a function of the leaving ability of the alkoxy group, as is demonstrated by a study of a series of phthalate monoesters ... 

As PEs are rapidly metabolized, measurement of the metabolites is generally accepted when the amount of exposure to humans is evaluated. PEs are mainly metabolized into phthalate monoesters and excreted into the urine (Fig. 1). Albro and Lavenhar reported 30 or more metabolites of DEHP metabolism. The exposure amount of mono(2-ethylhydroxyhexyl) phthalate (MEHHP) in which mono(2-ethylhexyl) phthalate (MEHP) is subjected to oxidation by co-1 and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) that is an oxide of MEHHP, etc. has been reported. MEHP oxides such as MEHHP and MEOHP were excreted into the urine at a high ratio compared to MEHP, when they were measured after DEHP exposure.It is known that PEs other than DEHP are metabolized into the mono form. The rate of metabolism is 69% when dibutyl phthalate is metabolized into monobutyl phthalate and 73% when dibutyl benzyl phthalate is metabolized into monobutyl benzyl phthalate. Because it is considered... 

PEs. This project reported the analysis " of 8 phthalate monoesters, which are the metabolites of PEs, and the simultaneous analysis of 11 PE metabolites when another metabolite is added using LC-atmospheric pressure chemical ionization (APCI)-MS/MS. In addition, electrospray ionization (ESI) and the use of LC-MS/MS for the simultaneous analysis of 15-16 materials related to PEs, including phthalic acid (PA) and an isomer, were reported.Fig. 2 shows the main chemicals used as biomarkers for the evaluation of the amount of exposure to PA. Epidemiologic analysis of exposure levels in healthy individuals and the effects on the human body was conducted using such exposure reports as those published by CDC. However, there are many unsolved problems, including the identification of exposure levels on a nationwide level and the evaluation of exposure in medical practice. Clearly, much work needs to be done. 

Fig. 1 Metabolic pathway of phthalate. Phthalates with R and R groups are metabohzed into phthalate monoesters, which are found in urine as glucuronide conjugates or free acids.

Yoshimura, M. Inoue, K. Hanaoka, T. Pan, G. Takahashi, K. Yamano, Y. Iwasaki, Y. Ito, R. Saito, K. Tsugane, S. Nakazawa, H. Development of simultaneous determination method of phthalate monoester metabolites in urine by LC/MS/MS and its application to assessment of phthalate-ester exposure. Bunseki Kagaku 2006, 55, 661. 

Differences in phthalate structure determine how they are metabolized and their toxic effects. MBuP and MBzP, metabolites of DBP and BBzP, have been identified as active metabolites toxic to reproductive endpoints, including sperm concentration in adult males (Hauser et al. 2006). Direct measures of parent phthalates or phthalate monoester metabolites in blood are difficult to interpret because of the high likelihood of contamination from sampling or from lab materials given that esterase activity after sample collection can generate monoester metabolites in samples contaminated after collection (Calafat et al. 2013). 

Duty SM, Ackerman RM, Calafat AM et al (2005a) Personal care product use predicts urinary concentrations of some phthalate monoesters. Environ Health Perspect 113(11) 1530-1535 Duty SM, Calafat AM, Silva Ml et al (2005b) Phthalate ejqmsure and reproductive hramones in adult men. Hum Reprod 20(3) 604-610... 

Hauser R, Meeker JD, Park S et al (2004) Temporal variability of urinary phthalate metabolite levels in men of reproductive age. Environ Health Perspect 112(17) 1734-1740 Hauser R, Meeker JD, Duty S et al (2006) Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiology 17(6) 682-691 Health and Consumer Protection (2007) Preliminary report on the safety of medical devices containing DEHP plasticized PVC or other plasticizers on neonates and other groups possibly at risk. European Commission, http //ec.europa.eu/health/ph risk/committees/04 scenihr/ docs/scenihr o 008.pdf. Accessed 15 Nov 2013 Helm D (2007) Correlation between production amounts of DEHP and daily intake. Sci Total Environ 388(l-3) 389-391... 

Hurst CH, Waxman DJ (2003) Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicol Sci 74(2) 297—308 Integrated Risk Information System (1997) Di(2-ethyUiexyl)phthalate (DEHP) summary. United States Environmental Protection Agency, http //www.epa.gov/iris/subst/0014.htm. Accessed 18 Nov 2013... 

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