Derivation of Biomonitoring Equivalents for di-n-butyl phthalate (DBP), benzylbutyl phthalate (BzBP), and diethyl phthalate (DEP).

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline, and are derived by integrating available data on pharmacokinetics with existing chemical risk assessments. This study reviews available health-based exposure guidance values for di-n-butyl phthalate (DBP), benzylbutyl phthalate (BzBP), and diethyl phthalate (DEP) from Health Canada, the United States Environmental Protection Agency (U.S. EPA), the Agency for Toxic Substances and Disease Registry (ATSDR), and the European Food Safety Authority (EFSA). BE values corresponding to the oral reference dose (RfD), minimal risk level (MRL) or tolerable daily intake (TDI) estimates from these agencies were derived for each compound based on data on excretion fractions of key urinary metabolites. These values may be used as screening tools for evaluation of biomonitoring data for metabolites of these three phthalate compounds in the context of existing risk assessments and for prioritization of the potential need for additional risk assessment efforts for each of these compounds relative to other chemicals.

[1]  R A Becker,et al.  Biomonitoring equivalents: a screening approach for interpreting biomonitoring results from a public health risk perspective. , 2007, Regulatory toxicology and pharmacology : RTP.

[2]  Shoma Berkemeyer,et al.  Longitudinal examination of 24-h urinary iodine excretion in schoolchildren as a sensitive, hydration status-independent research tool for studying iodine status. , 2006, The American journal of clinical nutrition.

[3]  R. Henderson,et al.  NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di-n-butyl phthalate. , 2002, Reproductive toxicology.

[4]  Conrad Brunk,et al.  Guidelines for the derivation of Biomonitoring Equivalents: report from the Biomonitoring Equivalents Expert Workshop. , 2008, Regulatory toxicology and pharmacology : RTP.

[5]  Holger M Koch,et al.  A simple pharmacokinetic model to characterize exposure of Americans to Di-2-ethylhexyl phthalate , 2010, Journal of Exposure Science and Environmental Epidemiology.

[6]  Holger M. Koch,et al.  New metabolites of di(2-ethylhexyl)phthalate (DEHP) in human urine and serum after single oral doses of deuterium-labelled DEHP , 2005, Archives of Toxicology.

[7]  C Springall,et al.  A biomarker approach to measuring human dietary exposure to certain phthalate diesters , 2001, Food additives and contaminants.

[8]  B. Lake,et al.  The in vitro hydrolysis of some phthalate diesters by hepatic and intestinal preparations from various species. , 1977, Toxicology and applied pharmacology.

[9]  Holger M Koch,et al.  Internal exposure of the general population to DEHP and other phthalates--determination of secondary and primary phthalate monoester metabolites in urine. , 2003, Environmental research.

[10]  Conrad Brunk,et al.  Guidelines for the communication of Biomonitoring Equivalents: report from the Biomonitoring Equivalents Expert Workshop. , 2008, Regulatory toxicology and pharmacology : RTP.

[11]  J. Brock,et al.  Quantitative detection of nine phthalate metabolites in human serum using reversed-phase high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. , 2003, Journal of analytical toxicology.

[12]  M. O'Rourke,et al.  Pesticide exposure and creatinine variation among young children , 2000, Journal of Exposure Analysis and Environmental Epidemiology.

[13]  R. Henderson,et al.  NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di-isononyl phthalate. , 2002, Reproductive toxicology.

[14]  Jerry L. Campbell,et al.  Kinetics of selected di-n-butyl phthalate metabolites and fetal testosterone following repeated and single administration in pregnant rats. , 2009, Toxicology.

[15]  Bruce H Alexander,et al.  Agreement of pesticide biomarkers between morning void and 24-h urine samples from farmers and their children , 2007, Journal of Exposure Science and Environmental Epidemiology.

[16]  K. Hungerbühler,et al.  What Are the Sources of Exposure to Eight Frequently Used Phthalic Acid Esters in Europeans? , 2006, Risk analysis : an official publication of the Society for Risk Analysis.

[17]  Dana B Barr,et al.  Estimating pesticide dose from urinary pesticide concentration data by creatinine correction in the Third National Health and Nutrition Examination Survey (NHANES-III) , 2004, Journal of Exposure Analysis and Environmental Epidemiology.

[18]  N. Skakkebaek,et al.  Urinary excretion of phthalates and paraben after repeated whole-body topical application in humans. , 2008, International journal of andrology.

[19]  R Tardif,et al.  A PBPK modeling-based approach to account for interactions in the health risk assessment of chemical mixtures. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[20]  T. Remer,et al.  Anthropometry-based reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research. , 2002, The American journal of clinical nutrition.

[21]  Sean M Hays,et al.  Derivation of Biomonitoring Equivalents for di(2-ethylhexyl)phthalate (CAS No. 117-81-7). , 2009, Regulatory toxicology and pharmacology : RTP.

[22]  Jesper Kristiansen,et al.  Comparison of uncertainties related to standardization of urine samples with volume and creatinine concentration. , 2004, The Annals of occupational hygiene.

[23]  R. Henderson,et al.  NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di-n-octyl phthalate. , 2002, Reproductive toxicology.

[24]  J. Furr,et al.  Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[25]  Samuel P. Caudill,et al.  Urinary Creatinine Concentrations in the U.S. Population: Implications for Urinary Biologic Monitoring Measurements , 2004, Environmental health perspectives.

[26]  I R Rowland,et al.  Hydrolysis of phthalate esters by the gastro-intestinal contents of the rat. , 1977, Food and cosmetics toxicology.

[27]  K Krishnan,et al.  Physiologically based modeling of the maximal effect of metabolic interactions on the kinetics of components of complex chemical mixtures. , 2000, Journal of toxicology and environmental health. Part A.

[28]  Melvin E Andersen,et al.  Tissue exposures to free and glucuronidated monobutylyphthalate in the pregnant and fetal rat following exposure to di-n-butylphthalate: evaluation with a PBPK model. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[29]  L Earl Gray,et al.  Mechanisms of action of phthalate esters, individually and in combination, to induce abnormal reproductive development in male laboratory rats. , 2008, Environmental research.

[30]  A. M. Api,et al.  Toxicological profile of diethyl phthalate: a vehicle for fragrance and cosmetic ingredients. , 2001, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[31]  R. Henderson,et al.  NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate. , 2002, Reproductive toxicology.

[32]  A. Calafat,et al.  Metabolite profiles of di-n-butyl phthalate in humans and rats. , 2007, Environmental science & technology.

[33]  W. Krol,et al.  Pharmacokinetics of dibutylphthalate in pregnant rats. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[34]  J. Brock,et al.  Quantitative detection of eight phthalate metabolites in human urine using HPLC-APCI-MS/MS. , 2000, Analytical chemistry.

[35]  J. Furr,et al.  A mixture of five phthalate esters inhibits fetal testicular testosterone production in the sprague-dawley rat in a cumulative, dose-additive manner. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[36]  Paul Tobback,et al.  Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food (AFC) on a request from the Commission , 2008 .

[37]  Sean M Hays,et al.  Using Biomonitoring Equivalents to interpret human biomonitoring data in a public health risk context , 2009, Journal of applied toxicology : JAT.

[38]  L. Bankir,et al.  Sex difference in urine concentration across differing ages, sodium intake, and level of kidney disease. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[39]  Volker Mersch-Sundermann,et al.  Phthalates: toxicology and exposure. , 2007, International journal of hygiene and environmental health.

[40]  Richard A Fenske,et al.  Comparison of organophosphorus pesticide metabolite levels in single and multiple daily urine samples collected from preschool children in Washington State , 2005, Journal of Exposure Analysis and Environmental Epidemiology.

[41]  R. Henderson,et al.  NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of butyl benzyl phthalate. , 2002, Reproductive toxicology.

[42]  Antonia M. Calafat,et al.  Integrating Biomonitoring Exposure Data into the Risk Assessment Process: Phthalates [Diethyl Phthalate and Di(2-ethylhexyl) Phthalate] as a Case Study , 2006, Environmental health perspectives.