Exposure to Phthalate Esters.

The American Chemistry Council Phthalate Esters Panel read with great interest the paper by Blount et al. (1) regarding urinary levels of phthalate ester metabolites in a sample set of the Third National Health and Nutrition Examination Survey (NHANES III) population. We have known for some time of this research, and have provided whatever information and assistance we could to the Centers for Disease Control and Prevention (CDC). The paper presents some interesting and informative data on the likely exposure levels of phthalate esters, which are summarized below:

* We believe that the data are analytically sound in that the CDC measured a physiologically relevant metabolite of the phthalate monoester as opposed to many investigators who have measured phthalate diester in biological samples (blood and tissues) as a biomonitor of exposure. Measurement of phthalate diesters in biological samples is highly subject to false positives from laboratory contamination.

* The CDC data measure urinary concentrations of phthalate monoesters, not the daily intake of phthalate esters. Although these measurements establish a good basis for biomonitoring, further calculations are needed to relate them to doses (below which we do not expect to see effects) developed from animal toxicology studies, such as U.S. Environmental Protection Agency (U.S. EPA) reference doses (RfDs), in order to place them into the risk assessment paradigm. Studies being conducted by the U.K. Ministry of Agriculture, Food, and Fisheries provide a key piece of information, namely, the molar ratio of phthalate ester metabolite in the urine of human volunteers given known amounts of phthalate ester (2). With this information, the CDC data can be converted to intake levels using the equation below by substituting the creatinine-corrected concentrations of monoester and a maximum output of 20 mg creatinine/kg/day for an adult female (range of 11-20 mg creatinine/kg/day) (3).

Daily intake (mg/ kg/ day)

= Urine concentration (mg/g creatine)

[equivalence] Creatine excretion (g/kg/day)

[equivalence] MW diester (g/mol)

/ MW monoester (g/mol)

[equivalence] Monoester in urine (mol)/ Diester ingested (mol)

* Using this conversion, the data indicate that the 95th percentile value of daily intake in all cases, except for diethyl phthalate (DEP), is below the estimated intake values established by the Agency for Toxic Substances and Disease Registry (ATSDR; Atlanta, GA), the International Programme on Chemical Safety (IPCS; Geneva, Switzerland), or the European Union (EU) risk assessment as illustrated in Table 1 (95th percentile vs. estimated intake). Furthermore, the highest values obtained (including for DEP) are at or below levels that the U.S. EPA has determined to be safe for daily exposures to these phthalates (estimated intake vs. RfD).

Table 1. Intake levels.

                         95th       Highest   Estimated
Phthalate      GM      Percentile    value     intake     RfD

DEP         12.34(a)     93.33      242.81      57(b)     800
DBP          1.56         6.87      116.96       7        100
BBP          0.73         3.34       19.79       6        200
DEHP         0.60         3.05       38.48      30(c)      20
DINP         0.21         1.08       14.35      10.8       ND

ND, not determined.

(a) All values in [micro]g/kg/day based on a maximum creatinine clearance of 20 mg/kg/day.

(b) Estimated intake taken from ATSDR, IPCS, or EU draft risk assessments.

(c) From Doull et al. (4) using ATSDR estimates.

* The highest value for total environmental exposure to the two most widely used plasticizers, di-(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DINP), are at or below the levels estimated by various governmental agencies. Thus, environmental exposure to the two phthalate esters used in most polyvinyl chloride (PVC) consumer products (toys, shower curtains, etc.) is very low.

* The CDC data also show what appear to be higher levels of exposure of DEP, dibutyl phthalate (DBP), and butylbenzyl phthalate (BBP), a fact that has received attention. DEP, DBP, and BBP are used in some personal care products (6,7). Each of these phthalate esters also has Food and Drug Administration approved uses in food packaging and processing materials (8). Therefore, it is not surprising that urinary levels of these phthalate esters may be higher relative to those used only in PVC.

* As indicated by Blount et al. (1), all available pharmacokinetic data on phthalate esters indicate that they are rapidly metabolized and excreted from the body, and there is no concern that these materials bioaccumulate.

We recognize that the study reported by Blount et al. (1) is only a pilot project for a larger-scale biomonitoring program, and we look forward to the continued research in this area. We believe the CDC data demonstrate that environmental exposure to high molecular weight phthalates is negligible. For the low molecular weight phthalates, with potential exposures other than PVC plastics, the data indicate that exposures are within previously determined exposure estimates and below developed RfDs. Phthalate esters have been used for more than 50 years (nearly 100 years in the case of DBP) without direct evidence of adverse human health effects. Although there are data for effects in rodents after exposure to phthalate esters, there are significant differences between rodents and primates in the pharmacokinetics and effects of these substances.

REFERENCES AND NOTES

(1.) Blount BC, Silva MJ, Caudill SP, Needham LL, Pirkle JL, Sampson EJ, Lucier GW, Jackson RJ, Brock JW. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect 108:979-982 (2000).

(2.) Anderson W. Ayesh R, Castle L, Scotter M, Springall C. A biomarker approach to quantify human dietary exposure to phthalates, risk assessment and communication for food safety [Abstract]. Presented at the First Joint CSL/JIFSAN Symposium on Food Safety & Nutrition, 20-22 June 2000, Central Science Laboratory, Sand Hutton, York, UK.

(3.) Tietz NW, ed. Textbook of Clinical Chemistry. Philadelphia, PA:W.B. Saunders Co., 1986;1821.

(4.) Doull J, Cattley R, Elcombe E, Lake BG, Swenberg J, Wilkinson C, Williams G, van Gemert M. A cancer risk assessment of di(2-ethylhexyl)phthalate: application of the new U.S. EPA risk assessment guidelines. Regul Toxicol Pharmacol 29:327-357 (1999).

(5.) Integrated Risk Information System (IRIS) database. Available http://www.epa.gov/ngisgm3/iris [cited 1990].

(6.) Brandt K. Cosmetic ingredient review on DEP and DBP. J Am Coll Toxicol 4:267-303 (1985).

(7.) Skinner JP. Final report on the safety assessment of butyl benzyl phthalate. J Am Coll Toxicol 11:1-23 (1992).

(8.) Food and Drug Administration, Department of Health and Human Services, 21 C.F.R [sections] 175-181, 1984.

Raymond M. David Toxicology Research Task Group Phthalate Esters Panel American Chemistry Council Arlington, Virginia