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Phthalates: Toxicology and exposure
ARTICLE IN PRESS
Int. J. Hyg. Environ. Health 210 (2007) 623–634 www.elsevier.de/ijheh
Phthalates: Toxicology and exposure Ursel Heudorfa,, Volker Mersch-Sundermannb, Ju¨rgen Angererc a
Public Health Department of the City of Frankfurt, Germany Department Indoor and Environmental Toxicology, University of Giessen, Germany c Institute and Optpatient Clinic of Occupational, Social, and Environmental Medicine, University of Erlangen-Nuremberg, Germany b
Abstract Phthalates are used as plasticizers in PVC plastics. As the phthalate plasticizers are not chemically bound to PVC, they can leach, migrate or evaporate into indoor air and atmosphere, foodstuff, other materials, etc. Consumer products containing phthalates can result in human exposure through direct contact and use, indirectly through leaching into other products, or general environmental contamination. Humans are exposed through ingestion, inhalation, and dermal exposure during their whole lifetime, including intrauterine development. This paper presents an overview on current risk assessments done by expert panels as well as on exposure assessment data, based on ambient and on current human biomonitoring results. Some phthalates are reproductive and developmental toxicants in animals and suspected endocrine disruptors in humans. Exposure assessment via modelling ambient data give hints that the exposure of children to phthalates exceeds that in adults. Current human biomonitoring data prove that the tolerable intake of children is exceeded to a considerable degree, in some instances up to 20-fold. Very high exposures to phthalates can occur via medical treatment, i.e. via use of medical devices containing DEHP or medicaments containing DBP phthalate in their coating. Because of their chemical properties exposure to phthalates does not result in bioaccumulation. However, health concern is raised regarding the developmental and/or reproductive toxicity of phthalates, even in environmental concentrations. r 2007 Elsevier GmbH. All rights reserved. Keywords: Phthalates; Toxicology; Exposure assessment; Human biomonitoring
Introduction Phthalates are used as plasticizers in PVC plastics. Therefore, many consumer products contain specific members of this family of chemicals, including building materials, household furnishings, clothing, cosmetics, pharmaceuticals, nutritional supplements, medical devices, dentures, children’s toys, glow sticks, modelling Corresponding author. Tel.: +49 69 21236980; fax: +49 69 21246247. E-mail address: [email protected] (U. Heudorf).
1438-4639/$ - see front matter r 2007 Elsevier GmbH. All rights reserved. doi:10.1016/j.ijheh.2007.07.011
clay, food packaging, automobiles, lubricants, waxes, cleaning materials and insecticides (ATSDR, 1995, 1997, 2001, 2002; NTP-CERHR, 2000, 2003a–f, 2005) (Table 1). Di-(2-ethylhexyl) phthalate (DEHP) is one of the most widespread phthalate plasticizer, used in numerous consumer products, commodities, and building materials. Additionally, DEHP is still used as plasticizer in medical products (US FDA, 2002; EC–CHCPD, 2002; ATSDR, 2002). Whereas in former years DEHP was the predominant used plasticizer with a production volume of 3–4 millions of tons worldwide (Wams, 1987), industrial production and use decreased
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Table 1.
U. Heudorf et al. / Int. J. Hyg. Environ. Health 210 (2007) 623–634
Use of phthalates (according to risk assessment of NTP CERHR, modified) Use
Di-ethyl-phthalate DEP Butyl benzyl phthalate BBP Di-n-butyl phthalate DBP Di(2-ethylhexyl)phthalate DEHP
Di-n-hexyl-phthalate DnHP Di-n-octyl-phthalate DnOP Di-isononyl phthalate DINP Di-isodecyl phthalate DIDP
Personal care products, cosmetics Vinyl tiles; food conveyor belts, artificial leather, automotive trim, traffic cones PVC plastics, latex adhesives, cosmetics, personal care products, cellulose plastics, solvent for dyes Building products (wallpaper, wire and cable insulation), car products (vinyl upholstery, car seats), clothing (footwear, raincoats), food packaging, children’s products (toys, grip bumpers), medical devices Dipmolded products, such as tool handles, dish-washer baskets; flooring, vinyl gloves, flea collars, conveyer belts used in food processing In mixtures C6–C10 phthalates: garden hoses, pool liners, flooring tiles, tarps Seam cements, bottle cap liners, conveyor belts (indirect food additive!) Garden hoses, pool liners, flooring tiles, tarps, toys PVC plastics, covering on wires and cables, artificial leather, toys, carpet backing, pool liners
in recent years. In 2003, more than 800 000 tons of phthalates have been used in Western Europe, 24% DEHP and more than 50% DINP (di-iso-nonylphthalate) and DIDP (di-iso-decylphthalate) (ECPI, 2004). Also other phthalates such as di-ethyl-phthalate (DEP), di-n-butyl phthalate (DBP), butyl benzyl phthalate (BBP), and di-n-octyl phthalate (DnOP) are widely used. As the phthalate plasticizers are not chemically bound to PVC, they can leach, migrate or evaporate into indoor air and atmosphere, foodstuff, other materials, etc. Consumer products containing phthalates can result in human exposure through direct contact and use, indirectly through leaching into other products, or general environmental contamination. Humans are exposed through ingestion, inhalation, and dermal exposure during their whole lifetime, including intrauterine development.
Toxicology Risk assessments on phthalates have been done by different expert panels in Europe and America, i.e. the European Chemicals Bureau (ECB, 2004), European Food Safety Authority (EFSA, 2004) European Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE, 1998a b, 2004), the US Agency for Toxic Substances and Disease Registry (ATSDR, 1995, 1997, 2001, 2002) and the Center for the Evaluation of Risks to Human Reproduction (NTPCERHR, 2000, 2003a–f, 2005), the US Environmental Protection Agency and International Agency on Research on Cancer (IARC, 2000). Phthalates exhibit low acute toxicity with LD 50 values of 1–30 g/kg bodyweight or with even higher concentrations. In short- and long-term rodent studies, dose-related adverse effects were found in liver, kidney,
and – for selected phthalates – also in thyroid gland tissue and testes. Significant differences could be detected in different species and between males and females. All phthalates have been tested negative for mutagenicity and/ or genotoxicity. With regard to carcinogenicity, the activity of DEP is questionable, for DiNP no hints for carcinogenicity were obtained, DBP seems to be associated with tumor promoting activity, and exposure to DEHP produced hepatocellular carcinoma in rodents along with a variety of other hepatocellular effects such as proliferation of peroxysomes and mitochondria, increase in Cyp4A1 and PCoA activities, liver tissue proliferation, suppression of apoptosis, etc. (NTP-CERHR, 2000). Most of these effects are mediated by an induction of the PPAR-alpha receptor. In PPAR-alpha knockout mice, administration of DEHP does not result in hepatocellular effects. Due to several reasons, e.g. differences in PPAR-alpha density, regulation and signalling pathways, adverse effects associated with PPAR activation in rodents do not occur in humans (NTP-CERHR, 2002, 2003a–f, 2005). Therefore, IARC recently reevaluated DEHP and changed its classification from ‘‘possible carcinogenic to humans’’ to ‘‘not classificable as to carcinogenicity in humans’’ (IARC, 2000). However, in recent years toxicological concerns rose regrading the possible endocrine disrupting potency of phthalates. The potential of phthalates to cause adverse effects on reproduction and development in humans was evaluated by the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR, 2000, 2003a–f, 2005). Seven phthalates were selected for evaluation because of high production volume, extent of human exposures, use in children’s products, and/or published evidence of reproductive or developmental toxicity (NTP-CERHR, 2000, 2003a–f, 2005) (Table 2). Because of lack of human data, studies
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Table 2.
625
Potential human reproductive and developmental effects of phthalates (NTP-CERHR, 2000, 2003a–f)
Human
Exposure assumption (mg/ kg bw/day)
Adverse effects
Serious concern Butyl benzyl phthalate BBP Di-n-butyl phthalate DBP Di(2-ethylhexyl)phthalate DEHP
Insufficient hazard and/ or exposure data Concern
2–10 1–30
D critically ill children, medical devices, males
R, children o1 years
D male fetuses of women undergoing certain medical treatments Di-n-hexylphthalate DnHP Di-n-octylphthalate DnOP Di-isononyl phthalate DINP pi-isodecyl Phthalate DIDP
Some concern
D, high exposure R, high doses male children 41 year
Minimal concern
Negligible concern
D
R (adult males) R (adults)
D
R (adult females)
R
R male offsprings during pregnancy
?
D/R
o30
R
?
D/R
o30
D
D
R
D, developmental effects; R, reproductive effects; bw, body weight.
with experimental animals were evaluated and the effects (NOAEL, LOAEL) were compared to available human exposure data and estimations, respectively. Based on these data, concerns were expressed that human exposure to phthalates may result in reduced sperm counts, histological changes in testes, and reduced fertility. In developmental studies effects such as increases in prenatal mortality, reduced growth and birth weight, skeletal, visceral, and external malformations were discussed as possibly associated with phthalate exposure. In two-generation studies possible effects such as reduced birth weight, decreased anogenital distance in males, reduced serum testosterone levels, decreased spermatocytes and other histopathological changes in the testes were described. Regarding DnHP, studies using high exposure dosages (9900 mg/kg bodyweight/day; 380–1670 mg/kg bodyweight/day) exhibited developmental and reproductive toxicity. However, because of the lack of studies with lower exposure, the panel concluded that there was insufficient information to reach a conclusion of the potential of this substance to adversely affect human development or reproduction. Animal studies with
DnOP showed no adverse effects up to 7500 mg/kg/ day, but in high exposure developmental studies (5000–10,000 mg/kg d) adverse effects were seen in all groups. No NOAEL could not be derived. Adverse effects on fetal development in laboratory animals could be seen in pregnant animals after exposure to 4100 mg DBP/kg bodyweight/day, 200 mg DIDP/kg bodyweight/day, 500–1000 mg DINP/kg bodyweight/ day, and 41000 mg BBP/kg bodyweight/day. Adverse reproductive effects in rats and mice were found in twogeneration studies with 143–285 mg DINP/kg bodyweight/day. Exposure to DBP showed developmental and reproductive toxicity already at exposure of 100 mg/ kg bodyweight/day. Mainly based on animal studies, it turned out that DEHP is the phthalate representative with the highest toxicity, resulting in the definition of specific risk groups such as children o1 year of age, critically ill children and pregnant women undergoing therapies or medical treatments using medical devices with DEHP (Table 2). Based on the NOAEL (and if necessary LOAEL) levels derived from animal studies, the Scientific Committee on Toxicity, Ecotoxicity and the Environment obtained
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Table 3.
U. Heudorf et al. / Int. J. Hyg. Environ. Health 210 (2007) 623–634
Risk assessment of phthalates (ATSDR, US-EPA, EU-CSTEE, Health Canada) Country, region
Committee, year
mg/kg bw/day
MRL/TDI/RfD
USA
ATSDR, 1995 US-EPA 1993a
7 5 0.8
MRL acute oral exposure MRL chronic oral exposure RfD chronic exposure
Canada EU
ATSDR, 2001 US-EPA 1990 Health Canada, 1994 CSTEE, 1998a, b
0.5 0.1 0.06 0.1
MRL acute oral exposure RfD chronic exposure TDI TDI
BBzP
USA EU
US-EPA 1993b CSTEE, 1998a, b
0.2 0.2
RfD chronic exposure TDI
DEHP
USA
US-EPA 1991 ATSDR, 2002
Canada EU
Health Canada, 1994 CSTEE, 1998a, b ECB/EU (RAR-DEHP), 2004?
0.020 0.100 0.060 0.044 0.050 0.020
RfD chronic exposure MRL intermediate duration exposure MRL chronic exposure TDI TDI TDI for newbornso3 months, women in childbearing age TDI infants 3-o12 months TDI population except newborns, infants, women in childbearing age MRL acute oral exposure MRL intermediate duration exposure TDI TDI TDI
DEP
DBP
USA
0.025 0.048 DnOP
USA
ATSDR, 1997
DiNP DiDP
EU EU EU
CSTEE, 1998a, b CSTEE, 1998a, b CSTEE, 1998a, b
3 0.4 0.37 0.15 0.25
MRL, minimal risk level; TDI, tolerable daily intake; RfD, reference dose levels.
tolerable daily intake values (TDI) for phthalates. Phthalates which are predominantly used such as DEHP (and DINP) are those with the lowest calculated TDI values (Table 3) (CSTEE, 1998a, 2004). The minimal risk levels (MRL), derived by the Agency for Toxic Substances and Disease Registry (ATSDR) are obtained by consideration of the most sensitive endpoint and the most sensitive species, using NOAEL or LOAEL levels and taking uncertainty factors into account. So, the lowest MRL of 0.06 mg/ kg/day had been calculated for chronic exposure to DEHP, based on a NOAEL of 5.8 mg/kg for adverse testicular effects, and an intermediate duration oral MRL based on a LOAEL of 140 mg/kg bodyweight for reduced fertility (ATSDR, 2002). The EPA derived a chronic RfD of 0.02 mg/day for DEHP based on a LOAEL of 19 mg/kg/day for hepatic effects in guinea pigs (IRIS, 2001).
Phthalates – ambient monitoring Due to the ubiquitous use of phthalates in numerous products and due to their ability to migrate into the various environmental compartments phthalates can be detected not only in consumer products, but also in food
and in the indoor environment resulting in contamination levels of indoor air and household dust. Several phthalates have been approved as indirect food additives, i.e. as adhesives and components of food wrapping (US FDA, 2000, 2003). In food stuff, phthalate levels are quite variable and packing materials are regarded as a relevant emission source (Page and Lacroix, 1995; Petersen and Breindahl, 2000). However, other sources could be detected: for instance, in Japan exposure via diet had been studied in duplicate food samples in 1999 and 2001. The plasticizers quantified were dibutyl phthalate, butylbenzyl phthalate (BBP), di(2-ethylhexyl) phthalate (DEHP), and diisononyl phthalate (DINP). In 1999, DEHP was found at the highest concentration among all phthalates with DEHP levels ranging between 10 and 4400 ng/g. Disposable PVC gloves used during the preparation of meals were suspected as one source of the high DEHP content. In 2001, significantly lower levels were found compared to those detected in 1999 (6–675 ng/g) (Tsumura et al., 2001, 2003). In household dust, levels of DEHP and DINP are generally exceeding those of high volatile phthalates such as DEP and DBP. In various studies median levels were: DEP o10 mg/kg, DBP 40–50 mg/kg, and DEHP 400–700 (max. 410,000) mg/kg (Becker et al., 2002;
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Fromme et al., 2004; Kersten and Reich, 2003; Po¨hner et al., 1998). This relation is inverse in indoor air, with median contamination levels: DEP 4350–650 ng/m3, DBP 600–1200 ng/m3 and DEHP 150–450 ng/m3 (Fromme et al., 2004; Holstrup and Butte, 2001; Sheldon et al., 1993). In infants and toddlers, polymer toys softened with phthalates were suspected as a potential source of phthalate exposure via mouthing activities. Estimates of DINP exposures ranged from 5 to 44 mg/kg bodyweight/day, with 99th percentiles up to 183 mg/kg bodyweight/day (Kavlock et al., 2002). For DEHP the calculation of exposure of children sucking or chewing toys or other articles of everyday use reached up to 85 mg/kg bodyweight/day (ATSDR, 2002). Considering the assumed toxicity of phthalates and the release rate from toys, the use of DnBP, BBzP, DEHP, DINP, and DIDP in toys intended for consumers younger than 3 years was prohibited in the EU in 1999 (COM, 1999). Whereas the use of consumer products and various other indoor sources are mainly responsible for the exposure to dimethyl, diethyl, dibutyl, benzylbutyl, diisononyl, and diisodecyl phthalate, foodstuffs represent the main exposure source for diisobutyl, dibutyl, and di-2-ethylhexyl phthalate (Wormuth et al., 2006; Schettler, 2006).
Exposure assessment by modelling ambient exposure data Based on those ambient monitoring data, exposure of the consumers has been estimated. The primary exposure to phthalates is from ingestion of foods, especially fatty foods such as milk, butter, and meats, but low-molecular weight phthalates (DEP, DBP, BBzP) may also be dermally absorbed, and the more volatile phthalates can be absorbed by inhalation (ATSDR, 1995, 2000). The exposure assessments of the NTPCERHR were: DBP 2–10 mg/kg bodyweight/day, DnOP and DIDP 530 mg/kg bodyweight/day and DEHP up to 30 mg kg bodyweight/day (NTP-CERHR, 2000, 2003a–f). Generally, the exposure of children to phthalates exceeds that in adults. Estimations of the daily intake of DEHP in the population of Canada in the early 1990s resulted in 9 mg/kg bodyweight/day for infants, 19 mg/kg bodyweight/day for toddlers, 14 mg/kg bodyweight/day in children and 6 mg/kg bodyweight in adults (Meek and Chan, 1994). A more detailed exposure assessment for European consumers according to scenario-based risk assessment approach (SceBRA) was recently published (Wormuth et al., 2006). Analyses of oral, dermal and inhalation pathways causing consumer exposure in Europe to eight different phthalates in the age groups infants, toddlers, children, teens and adults were done. Again, infants and
627
toddlers experienced higher daily exposure to all the phthalates investigated than teens or adults. In infants and toddlers, mean daily exposure to DINP and DIDP even was calculated to be higher than the maximum exposure to these phthalates in all other age groups investigated. Their maximum exposure to DEHP and DINP was higher than 100 mg/kg bodyweight/day, mainly by mouthing of soft plastic toys and the ingestion of food and dust. Obviously, the TDI for DEHP was exceeded and the range of the TDI for DINP was reached in a considerable percentage of infants (Table 4). Regarding the contribution of various sources to exposure in the different consumer groups, consistent patterns could be found for four of the eight phthalates: indoor air caused most of the exposure to DMP, the usage of personal care products such as skin care products, shampoos, etc., was predominant in the exposure to DEP, and food was the dominating source of exposure to DBP and DEHP (495%) – however, in infants and toddlers a certain amount of exposure to DBP and DEHP was caused by ingestion of dust or by mouthing as well (o20–30%). Concerning BBzP, DINP, and DIDP, sources of exposure varied extremely between infants/toddlers and adults: mouthing and ingestion of dust was found to be the main exposure source in infants/toddlers (475% BBzP, 495% DINP, DIDP), a source neglectible in adults (Wormuth et al., 2006).
Exposure assessment by human biomonitoring Another method of exposure assessment is to measure internal exposure, i.e. via analysis of the specific metabolites in urine. The relatively polar and lowmolecular-weight phthalates (e.g., DBP) primarily metabolize to their monoesters and are excreted (Albro and Moore, 1974; ATSDR, 1995, 2001), whereas the highermolecular-weight phthalates (e.g. DEHP, DnOP, DINP) are hydrolysed to their respective monoesters first, which, in a multistep pathway are metabolized to more hydrophilic oxidative metabolites (Albro et al., 1974). Major DEHP-metabolites known are: mono-(-2ethyl-5hexyl)phthalate (MEHP), mono-(-2ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono-(-2ethyl-5-oxohexyl) phthalate (5oxo-MEHP), mono-(-2ethyl-5-carboxypentyl) phthalate (5cx-MEPP), mono-[-2(carboxymethyl)hexyl] phthalate (2cx-MMHP); fast and reliable analytical methods for these compounds were developed recently (Koch et al., 2003a, 2005a; Silva et al., 2006a, b; Kato et al., 2003, 2004; Preuss et al., 2005). In consequence of the ubiquitous use and contamination with phthalates, phthalate metabolites can be detected in urine samples of the general population. Most of the published data have been obtained from
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2.68 50.94 1.61 18.57 1.89 16.32 0.29 0.09 92.38 0.22 1.15 0.45 3.61 0.31 2.85 0.00 0.00 8.59 2.54 64.93 1.45 38.56 1.65 14.71 0.26 0.08 124.17 0.22 1.43 0.41 3.53 0.27 2.54 0.00 0.00 8.42 6.28 4.44 1.25 17.01 1.24 17.44 5.61 0.47 53.73 0.49 0.76 0.29 1.23 0.06 1.97 0.19 0.03 5.00 9.72 8.31 2.62 25.42 3.67 62.10 67.19 4.24 183.28 0.76 1.49 0.68 2.55 0.31 6.31 7.07 0.51 19.68 23.46 19.74 5.58 44.92 7.56 135.28 135.02 8.99 380.57 1.81 3.48 1.57 7.60 0.76 16.16 21.98 1.43 54.80 DMP DEP DBP DnBP BBzP DEHP DINP DIDP Mean
Maximum (mg/ kg bw day) Mean (mg/ kg bw day) Maximum (mg/ kg bw day) Mean (mg/ kg bw day) Maximum (mg/ kg bw day) Mean (mg/ kg bw day) Maximum (mg/ kg bw day) Mean (mg/ kg bw day) Maximum (mg/ kg bw day) Mean (mg/ kg bw day)
Phthalate Infants 0–12 mo (5.5 kg bw)
Toddlers 1–3 years (13 kg bw)
Children 4–10 years (27 kg bw) Female adults 18–80 years (60 kg bw)
Male adults 18–80 years (70 kg bw)
U. Heudorf et al. / Int. J. Hyg. Environ. Health 210 (2007) 623–634
Table 4. Daily internal exposure to eight phthalates (in mg/kg bodyweight day) in 5 consumer groups, mean and maximal exposure – estimations based on ambient monitoring and scenario calculations for uptake of food, air, water, consumer products, household dust, leaching from toys, etc. (Wormuth et al., 2006)
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studies in Germany and the USA (Becker et al., 2004; Koch et al., 2003b, 2004a, b, 2005a–c, 2006; Kato et al., 2004; Silva et al., 2004; CDC, 2005) (Table 4). In the NHANES Study 1999–2000 children had higher levels of MBP, MBzP and MEHP, but had significant lower levels of MEP. Females had significantly higher levels of MEP and MBzP (monobenzyl phthalate) than men, but similar MEHP levels (Silva et al., 2004). The high levels of MEP were most likely associated with the everyday use of consumer products, that commonly contain DEP. Adults are more likely to use cosmetics than children; these data are consistent with the recent exposure assessment via ambient monitoring for Europeans (Wormuth et al., 2006). Compared to the NHANES data 1988–1994, a decrease in the metabolite levels MEP, MBP, MBzP and MEHP could be found (Barr et al., 2003) (Table 5). Because of the complex metabolization of DEHP, intake estimations solely based on the biomarker MEHP have drawbacks. MEHP is also formed out of DEHP by abiotic processes and therefore is an environmental contaminant of its own. Hence, MEHP cannot unambiguously discriminate between exposure and secondary cross contamination during sample handling and processing. Furthermore, the metabolite MEHP represents only less than 10% of the original DEHP dose, and it has the shortest half-life of elimination of the metabolites to be investigated. Recently, a study of the elimination characteristics of DEHP showed, that the major share of the metabolites excreted in urine after exposure to DEHP are the secondary metabolites. After 24 h, 67% of the DEHP dose was excreted in urine as five of the major metabolites 5-OH-MEHP (23.3%), 5cx-MEPP (18.5%), 5oxo-MEHP (15.0%), MEHP (5.9%) and 2cx-MMHP (4.2%). The oxidized DEHP metabolites exhibit considerably longer half-lives of elimination than the monoester MEHP: MEHP 5 h, 5OH-MEHP and 5oxo-MEHP 10 h, 5cx-MEPP 12–15 h and 2cx-MMHP 24 h (Koch et al., 2005a, 2006; Preuss et al., 2005). The long half-life of elimination makes 5cxMEPP and 2cx-MMHP excellent parameters to measure the time-weighted body burden to DEHP (Koch et al., 2006). 5-OH-MEHP and 5oxo-MEHP more reflect the short-term exposure (Koch et al., 2005a; Preuss et al., 2005). Furthermore, there are strong hints that the secondary oxydized DEHP metabolites, not DEHP or MEHP, are the ultimate developmental toxicants (Regnier et al., 2004; Stroheker et al., 2005). Therefore, the secondary oxidized DEHP metabolites are considered excellent and robust parameters for DEHP biomonitoring (Koch et al., 2006). With these analytical methods available, several studies in Germany as well as in the USA have been published using these parameters up to now (Table 6). Given the urinary levels of the secondary metabolites of DEHP and the ratio of these metabolites in urine,
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Table 5.
Monoester metabolite levels of phthalates in population samples from USA and Germany (mg/l)
Study, author
Year
NHANES, Blount et al. (2000) CDC (2003) NHANES Silva et al. (2004) Duty et al. (2005) Koch et al. (2003a, b) Koch et al. (2004a, b, 2005a–c)
1988–1994 1999–2000
1999–2003 2002 2003
n
Age (yr)
MEP median (P95)
MBP median (P95)
MBZP median (P95)
MEHP median (P95)
289
20–60
305.0 (3750)
41.0 (294)
21.2 (137)
2.7 (21.5)
328 753 1456 141 85 36
6–11 12–19 420 20–54 7–65 2.6–6.5
74.7 (756) 193.0 (3260) 180.0 (3480) 160.0 (2103) 90.2 (560.5) n.a.
40.0 (163) 36.1 (165) 23.0 (142) 16.2 (69.9) 181.2 (824.9) 139.0 (3058 max) 91.8 (184 max)
40.3 (214) 28.3 (125) 13.8 (86.3) 7.9 (38.4) 21.0 (145.7) 22.1 (164 max) 12.7 (39.4 max)
4.9 (34.5) 3.7 (22.8) 3.0 (22.4) 6.3 (112.0) 10.3 (37.9) 6.6 (14.6)
19
Table 6.
629
20–59
9.0 (29.0)
Mean body burden to DEHP, expressed in the urinary excretion of DEHP metabolites (in mg/l)
Author, year Population Koch et al., 2003a, b Barr et al., 2003 Becker et al., 2004 Kato et al., 2004 Preuss et al., 2005 Silva et al., 2006a, b CDC, 2005
Population
Year
Germany, random US, random Germany, pilot US, random
2002
2002
Germany, random USA
2005 2003–2004
USA
2001–2002
Special risk groups Koch et al., Germany 2005a–c Germany Koch et al., 2006 Calafat et al., 2004
USA
Number
Age
MEHP
5OHMEHP
5oxoMEHP
5cxMEPP
2cxMMHP
85
7–63
10.3
46.8
36.5
n.a
n.a.
62 254
3–14
4.5 7.2
35.9 52.1
28.3 41.4
n.a n.a
n.a. n.a.
oLOD
17.4
15.6
n.a
n.a.
Children, adults Adults (median) 6–11 years (geo mean) 12–19 years (geo mean) 420 years (geo mean)
9.8
47.5
39.7
85.5
36.6
3.1
15.3
7.1
15.6
5.9
4.40
33.6
23.34
n.a.
n.a.
4.57
24.9
17.5
4.20
18.1
12.0
Adult platelet donors Neonatal patients (25–40 week) Neonatal care patients
257
926
774
n.a.
n.a.
#
557*
406*
5 550*
129*
94.4
2 399
79.1
10 228
62.2
127 19 129
2004
18
2005
42
2003–2004
6
n.a., not analysed; #, dismissed, because external contamination could not be excluded; *P95.
internal exposure to DEHP can be calculated. Daily intake can be obtained by the formula: DI½mg=kg bw=day ¼
UE½mg=gCE½mg=kg bw=day MWD , F UE 1000½mg=g MWM
where DI is the daily intake; UE the urinary excretion (of the metabolite); CE the creatinin excretion normalized by body weight; FUE the ratio of urinary excretion to total elimination; MWD the molecular weight of diester; MWM the molecular weight of metabolite.
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In effect, intake of DEHP is higher in children than in adults. The TDI is exceeded to a considerable degree, in some instances up to 20-fold, and gives reason for concern (Becker et al., 2004; Koch et al., 2003b, 2006). Exposure assessment via humanbiomonitoring results in higher internal exposure values than via modelling ambient data, especially in children (Wormuth et al., 2006).
Special problems in risk groups – exposure via medical devices and medications Medical devices containing di-(2-ethylhexyl) phthalate are a source of significant exposure in a susceptible subpopulation of individuals, especially those undergoing intensive care, platelet transfusion, hemodialysis and extracorporal membrane oxygenation (ECMO) in newborns (Schettler, 2006). Using heparinized PVC/ DEHP tubing, DEHP exposure from ECMO could be reduced considerably (Karle et al., 1997). Nevertheless exposure assessment via modelling resulted in very high levels of exposure of persons medically treated with PVC tubing; with the highest exposures in newborns undergoing ECMO (410 mg/kg bodyweight/day) (Table 7). These calculations could be confirmed by human biomonitoring studies in recent years, showing very high metabolite levels after platelet transfusion as well as in newborns undergoing intensive care therapy, etc. (Koch et al., 2005b, c; Silva et al., 2006a) (Table 6). Therefore, exposure to DEHP via medical devices, especially exposures of intensively treated infants or children can approach toxic doses in rodents, which
Table 7. Intravenous exposure to DEHP from selected medical procedures using medical devices of PVC containing DEHP (modified from US FDA, 2002) Adult DEHP (mg/kg bw day) Crystalloid i.v. solutions Total parenteral nutrition Without added lipid With added lipid Blood transfusion Trauma patient Transfusion/ ECMO Exchange transfusion Replacement transfusion
Neonate DEHP (mg/kg bw day)
0.005
0.03
0.03
0.03
0.13
2.5
8.5 3.0
14.0 22.6 0.3
leads to great concern (NTP-CERHR, 2000). Risk assessments were published by Latini et al. (2004) and Tickner et al. (2001), but also by institutions such as US FDA (2002), Health Canada (2002), and the European Commission (2002). As a result, there are no indications that neonates of high DEHP exposure have any altered long-term fertility patterns. An evaluation of adolescents exposed to significant quantities of DEHP as neonates via ECMO showed no significant adverse effects on their physical growth and pubertal maturity: thyroid, liver, renal, and male and female gonadal functions tested were within normal range for age and sex distribution (Rais-Bahrami et al., 2004). This does not prove, of course, that there is no risk. At present there is no evidence that recipients of repeated blood transfusions experience DEHP-related adverse effects (EU, 2002). In any consideration of restrictions on the use of PVC materials in medical devices, full account must be taken of the actual benefits of these materials and the balance between these benefits and risks (EU, 2002). The most detailed recommendations have been published by Health Canada (2002) (i.e. alternative products such as heparin-coated tubes should be used for all ECMO procedures in neonates and infants), tubing and storage bags used for the administration of lipophilic drugs that contain surfactants should not contain DEHP, and total parenteral nutrition (TPN) solutions should be administered to newborns and infants only via products that do not contain DEHP. Furthermore, research into further methods for reducing the release of DEHP from medical products should be urgently encouraged (Health Canada, 2002). Another potential source of exposure is medication. The need for site-specific dosage medications has led to the use of enteric coatings that allow the release of the active ingredients into the small intestine or in the colon. The enteric coatings generally consist of various polymers that contain plasticizers, including phthalates such as diethyl phthalate (DEP) and dibutyl phthalate (DBP) (Hauser et al., 2004). These substances are approved as inert ingredients in medications (US FDA, 2000, 2003). In a 30-year-old male with a medical history of ulcerative colitis and taking of Asacol–antiinflammatory remedy mesalamin as a delayed release tablet – urinary levels of MEP and MBP, the mono esters of DEP and DBP, were more than two orders of magnitude higher than the 95th percentile for males reported in the National Health and Nutrition Examination Survey (NHANES) (Hauser et al., 2004). DBP may also be an ingredient in cellulose acetate free films for transdermal use (Rao and Diwan, 1997). DBP is currently used in 64 pharmaceutical products in Germany, among others in common bronchiolytics for children and adults. In one out of 36 nursery school children studied for internal exposure to DBP and DBzP a urinary level of 2249 mg MBP/g creatinine could be
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found, caused by medication. This maximum concentration was approximately 15 times higher than that for the adults tested (Koch et al., 2005d). Intake of four tablets of a DBP-containing drug (which can be bought without prescription) by a male volunteer led to an internal exposure of 402 mg DBP/kg bodyweight, thus exceeding 4-fold the TDI value for adult women (Koch et al., 2005e). Therefore, the use of pharmaceutical drugs containing DBP should be omitted whenever possible in children and in women capable of childbearing for preventive reasons (Koch et al., 2005e).
Conclusion Phthalates are used worldwide as plasticizers in PVC materials. Many consumer products contain specific representatives of this family, resulting in ubiquitous exposure of the population. Though foodstuffs are regarded as the relevant source of exposure to the general population, in special risks groups other sources such as medical devices may be predominant. Especially in children, TDI is exceeded to a considerable degree. High exposures to phthalates can occur via medical treatment, i.e. via use of medical devices containing DEHP or pharmaceutical drugs containing DBP phthalate in their coating. Because of their chemical properties, exposure to phthalates does not result in bioaccumulation. However, health concern regarding the developmental and/or reproductive toxicity of phthalates can be raised not only on the basis of results of animal experiments but also under consideration of recently published human studies (Duty et al., 2005; Swan et al., 2005; Marsee et al., 2006), even in ambient concentrations. Further studies are necessary to shed light on possible mechanisms of action of developmental and/or reproductive effects caused by phthalates in humans.
Note added in proof After the manuscript had been finished, new data human biomonitoring of phthalates have been published in addition to those cites in the text: Fromme et al., 2007; Wittassek et al., 2007a,b.
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Int. J. Hyg. Environ. Health 210 (2007) 623–634 www.elsevier.de/ijheh
Phthalates: Toxicology and exposure Ursel Heudorfa,, Volker Mersch-Sundermannb, Ju¨rgen Angererc a
Public Health Department of the City of Frankfurt, Germany Department Indoor and Environmental Toxicology, University of Giessen, Germany c Institute and Optpatient Clinic of Occupational, Social, and Environmental Medicine, University of Erlangen-Nuremberg, Germany b
Abstract Phthalates are used as plasticizers in PVC plastics. As the phthalate plasticizers are not chemically bound to PVC, they can leach, migrate or evaporate into indoor air and atmosphere, foodstuff, other materials, etc. Consumer products containing phthalates can result in human exposure through direct contact and use, indirectly through leaching into other products, or general environmental contamination. Humans are exposed through ingestion, inhalation, and dermal exposure during their whole lifetime, including intrauterine development. This paper presents an overview on current risk assessments done by expert panels as well as on exposure assessment data, based on ambient and on current human biomonitoring results. Some phthalates are reproductive and developmental toxicants in animals and suspected endocrine disruptors in humans. Exposure assessment via modelling ambient data give hints that the exposure of children to phthalates exceeds that in adults. Current human biomonitoring data prove that the tolerable intake of children is exceeded to a considerable degree, in some instances up to 20-fold. Very high exposures to phthalates can occur via medical treatment, i.e. via use of medical devices containing DEHP or medicaments containing DBP phthalate in their coating. Because of their chemical properties exposure to phthalates does not result in bioaccumulation. However, health concern is raised regarding the developmental and/or reproductive toxicity of phthalates, even in environmental concentrations. r 2007 Elsevier GmbH. All rights reserved. Keywords: Phthalates; Toxicology; Exposure assessment; Human biomonitoring
Introduction Phthalates are used as plasticizers in PVC plastics. Therefore, many consumer products contain specific members of this family of chemicals, including building materials, household furnishings, clothing, cosmetics, pharmaceuticals, nutritional supplements, medical devices, dentures, children’s toys, glow sticks, modelling Corresponding author. Tel.: +49 69 21236980; fax: +49 69 21246247. E-mail address: [email protected] (U. Heudorf).
1438-4639/$ - see front matter r 2007 Elsevier GmbH. All rights reserved. doi:10.1016/j.ijheh.2007.07.011
clay, food packaging, automobiles, lubricants, waxes, cleaning materials and insecticides (ATSDR, 1995, 1997, 2001, 2002; NTP-CERHR, 2000, 2003a–f, 2005) (Table 1). Di-(2-ethylhexyl) phthalate (DEHP) is one of the most widespread phthalate plasticizer, used in numerous consumer products, commodities, and building materials. Additionally, DEHP is still used as plasticizer in medical products (US FDA, 2002; EC–CHCPD, 2002; ATSDR, 2002). Whereas in former years DEHP was the predominant used plasticizer with a production volume of 3–4 millions of tons worldwide (Wams, 1987), industrial production and use decreased
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Table 1.
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Use of phthalates (according to risk assessment of NTP CERHR, modified) Use
Di-ethyl-phthalate DEP Butyl benzyl phthalate BBP Di-n-butyl phthalate DBP Di(2-ethylhexyl)phthalate DEHP
Di-n-hexyl-phthalate DnHP Di-n-octyl-phthalate DnOP Di-isononyl phthalate DINP Di-isodecyl phthalate DIDP
Personal care products, cosmetics Vinyl tiles; food conveyor belts, artificial leather, automotive trim, traffic cones PVC plastics, latex adhesives, cosmetics, personal care products, cellulose plastics, solvent for dyes Building products (wallpaper, wire and cable insulation), car products (vinyl upholstery, car seats), clothing (footwear, raincoats), food packaging, children’s products (toys, grip bumpers), medical devices Dipmolded products, such as tool handles, dish-washer baskets; flooring, vinyl gloves, flea collars, conveyer belts used in food processing In mixtures C6–C10 phthalates: garden hoses, pool liners, flooring tiles, tarps Seam cements, bottle cap liners, conveyor belts (indirect food additive!) Garden hoses, pool liners, flooring tiles, tarps, toys PVC plastics, covering on wires and cables, artificial leather, toys, carpet backing, pool liners
in recent years. In 2003, more than 800 000 tons of phthalates have been used in Western Europe, 24% DEHP and more than 50% DINP (di-iso-nonylphthalate) and DIDP (di-iso-decylphthalate) (ECPI, 2004). Also other phthalates such as di-ethyl-phthalate (DEP), di-n-butyl phthalate (DBP), butyl benzyl phthalate (BBP), and di-n-octyl phthalate (DnOP) are widely used. As the phthalate plasticizers are not chemically bound to PVC, they can leach, migrate or evaporate into indoor air and atmosphere, foodstuff, other materials, etc. Consumer products containing phthalates can result in human exposure through direct contact and use, indirectly through leaching into other products, or general environmental contamination. Humans are exposed through ingestion, inhalation, and dermal exposure during their whole lifetime, including intrauterine development.
Toxicology Risk assessments on phthalates have been done by different expert panels in Europe and America, i.e. the European Chemicals Bureau (ECB, 2004), European Food Safety Authority (EFSA, 2004) European Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE, 1998a b, 2004), the US Agency for Toxic Substances and Disease Registry (ATSDR, 1995, 1997, 2001, 2002) and the Center for the Evaluation of Risks to Human Reproduction (NTPCERHR, 2000, 2003a–f, 2005), the US Environmental Protection Agency and International Agency on Research on Cancer (IARC, 2000). Phthalates exhibit low acute toxicity with LD 50 values of 1–30 g/kg bodyweight or with even higher concentrations. In short- and long-term rodent studies, dose-related adverse effects were found in liver, kidney,
and – for selected phthalates – also in thyroid gland tissue and testes. Significant differences could be detected in different species and between males and females. All phthalates have been tested negative for mutagenicity and/ or genotoxicity. With regard to carcinogenicity, the activity of DEP is questionable, for DiNP no hints for carcinogenicity were obtained, DBP seems to be associated with tumor promoting activity, and exposure to DEHP produced hepatocellular carcinoma in rodents along with a variety of other hepatocellular effects such as proliferation of peroxysomes and mitochondria, increase in Cyp4A1 and PCoA activities, liver tissue proliferation, suppression of apoptosis, etc. (NTP-CERHR, 2000). Most of these effects are mediated by an induction of the PPAR-alpha receptor. In PPAR-alpha knockout mice, administration of DEHP does not result in hepatocellular effects. Due to several reasons, e.g. differences in PPAR-alpha density, regulation and signalling pathways, adverse effects associated with PPAR activation in rodents do not occur in humans (NTP-CERHR, 2002, 2003a–f, 2005). Therefore, IARC recently reevaluated DEHP and changed its classification from ‘‘possible carcinogenic to humans’’ to ‘‘not classificable as to carcinogenicity in humans’’ (IARC, 2000). However, in recent years toxicological concerns rose regrading the possible endocrine disrupting potency of phthalates. The potential of phthalates to cause adverse effects on reproduction and development in humans was evaluated by the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR, 2000, 2003a–f, 2005). Seven phthalates were selected for evaluation because of high production volume, extent of human exposures, use in children’s products, and/or published evidence of reproductive or developmental toxicity (NTP-CERHR, 2000, 2003a–f, 2005) (Table 2). Because of lack of human data, studies
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Table 2.
625
Potential human reproductive and developmental effects of phthalates (NTP-CERHR, 2000, 2003a–f)
Human
Exposure assumption (mg/ kg bw/day)
Adverse effects
Serious concern Butyl benzyl phthalate BBP Di-n-butyl phthalate DBP Di(2-ethylhexyl)phthalate DEHP
Insufficient hazard and/ or exposure data Concern
2–10 1–30
D critically ill children, medical devices, males
R, children o1 years
D male fetuses of women undergoing certain medical treatments Di-n-hexylphthalate DnHP Di-n-octylphthalate DnOP Di-isononyl phthalate DINP pi-isodecyl Phthalate DIDP
Some concern
D, high exposure R, high doses male children 41 year
Minimal concern
Negligible concern
D
R (adult males) R (adults)
D
R (adult females)
R
R male offsprings during pregnancy
?
D/R
o30
R
?
D/R
o30
D
D
R
D, developmental effects; R, reproductive effects; bw, body weight.
with experimental animals were evaluated and the effects (NOAEL, LOAEL) were compared to available human exposure data and estimations, respectively. Based on these data, concerns were expressed that human exposure to phthalates may result in reduced sperm counts, histological changes in testes, and reduced fertility. In developmental studies effects such as increases in prenatal mortality, reduced growth and birth weight, skeletal, visceral, and external malformations were discussed as possibly associated with phthalate exposure. In two-generation studies possible effects such as reduced birth weight, decreased anogenital distance in males, reduced serum testosterone levels, decreased spermatocytes and other histopathological changes in the testes were described. Regarding DnHP, studies using high exposure dosages (9900 mg/kg bodyweight/day; 380–1670 mg/kg bodyweight/day) exhibited developmental and reproductive toxicity. However, because of the lack of studies with lower exposure, the panel concluded that there was insufficient information to reach a conclusion of the potential of this substance to adversely affect human development or reproduction. Animal studies with
DnOP showed no adverse effects up to 7500 mg/kg/ day, but in high exposure developmental studies (5000–10,000 mg/kg d) adverse effects were seen in all groups. No NOAEL could not be derived. Adverse effects on fetal development in laboratory animals could be seen in pregnant animals after exposure to 4100 mg DBP/kg bodyweight/day, 200 mg DIDP/kg bodyweight/day, 500–1000 mg DINP/kg bodyweight/ day, and 41000 mg BBP/kg bodyweight/day. Adverse reproductive effects in rats and mice were found in twogeneration studies with 143–285 mg DINP/kg bodyweight/day. Exposure to DBP showed developmental and reproductive toxicity already at exposure of 100 mg/ kg bodyweight/day. Mainly based on animal studies, it turned out that DEHP is the phthalate representative with the highest toxicity, resulting in the definition of specific risk groups such as children o1 year of age, critically ill children and pregnant women undergoing therapies or medical treatments using medical devices with DEHP (Table 2). Based on the NOAEL (and if necessary LOAEL) levels derived from animal studies, the Scientific Committee on Toxicity, Ecotoxicity and the Environment obtained
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Table 3.
U. Heudorf et al. / Int. J. Hyg. Environ. Health 210 (2007) 623–634
Risk assessment of phthalates (ATSDR, US-EPA, EU-CSTEE, Health Canada) Country, region
Committee, year
mg/kg bw/day
MRL/TDI/RfD
USA
ATSDR, 1995 US-EPA 1993a
7 5 0.8
MRL acute oral exposure MRL chronic oral exposure RfD chronic exposure
Canada EU
ATSDR, 2001 US-EPA 1990 Health Canada, 1994 CSTEE, 1998a, b
0.5 0.1 0.06 0.1
MRL acute oral exposure RfD chronic exposure TDI TDI
BBzP
USA EU
US-EPA 1993b CSTEE, 1998a, b
0.2 0.2
RfD chronic exposure TDI
DEHP
USA
US-EPA 1991 ATSDR, 2002
Canada EU
Health Canada, 1994 CSTEE, 1998a, b ECB/EU (RAR-DEHP), 2004?
0.020 0.100 0.060 0.044 0.050 0.020
RfD chronic exposure MRL intermediate duration exposure MRL chronic exposure TDI TDI TDI for newbornso3 months, women in childbearing age TDI infants 3-o12 months TDI population except newborns, infants, women in childbearing age MRL acute oral exposure MRL intermediate duration exposure TDI TDI TDI
DEP
DBP
USA
0.025 0.048 DnOP
USA
ATSDR, 1997
DiNP DiDP
EU EU EU
CSTEE, 1998a, b CSTEE, 1998a, b CSTEE, 1998a, b
3 0.4 0.37 0.15 0.25
MRL, minimal risk level; TDI, tolerable daily intake; RfD, reference dose levels.
tolerable daily intake values (TDI) for phthalates. Phthalates which are predominantly used such as DEHP (and DINP) are those with the lowest calculated TDI values (Table 3) (CSTEE, 1998a, 2004). The minimal risk levels (MRL), derived by the Agency for Toxic Substances and Disease Registry (ATSDR) are obtained by consideration of the most sensitive endpoint and the most sensitive species, using NOAEL or LOAEL levels and taking uncertainty factors into account. So, the lowest MRL of 0.06 mg/ kg/day had been calculated for chronic exposure to DEHP, based on a NOAEL of 5.8 mg/kg for adverse testicular effects, and an intermediate duration oral MRL based on a LOAEL of 140 mg/kg bodyweight for reduced fertility (ATSDR, 2002). The EPA derived a chronic RfD of 0.02 mg/day for DEHP based on a LOAEL of 19 mg/kg/day for hepatic effects in guinea pigs (IRIS, 2001).
Phthalates – ambient monitoring Due to the ubiquitous use of phthalates in numerous products and due to their ability to migrate into the various environmental compartments phthalates can be detected not only in consumer products, but also in food
and in the indoor environment resulting in contamination levels of indoor air and household dust. Several phthalates have been approved as indirect food additives, i.e. as adhesives and components of food wrapping (US FDA, 2000, 2003). In food stuff, phthalate levels are quite variable and packing materials are regarded as a relevant emission source (Page and Lacroix, 1995; Petersen and Breindahl, 2000). However, other sources could be detected: for instance, in Japan exposure via diet had been studied in duplicate food samples in 1999 and 2001. The plasticizers quantified were dibutyl phthalate, butylbenzyl phthalate (BBP), di(2-ethylhexyl) phthalate (DEHP), and diisononyl phthalate (DINP). In 1999, DEHP was found at the highest concentration among all phthalates with DEHP levels ranging between 10 and 4400 ng/g. Disposable PVC gloves used during the preparation of meals were suspected as one source of the high DEHP content. In 2001, significantly lower levels were found compared to those detected in 1999 (6–675 ng/g) (Tsumura et al., 2001, 2003). In household dust, levels of DEHP and DINP are generally exceeding those of high volatile phthalates such as DEP and DBP. In various studies median levels were: DEP o10 mg/kg, DBP 40–50 mg/kg, and DEHP 400–700 (max. 410,000) mg/kg (Becker et al., 2002;
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Fromme et al., 2004; Kersten and Reich, 2003; Po¨hner et al., 1998). This relation is inverse in indoor air, with median contamination levels: DEP 4350–650 ng/m3, DBP 600–1200 ng/m3 and DEHP 150–450 ng/m3 (Fromme et al., 2004; Holstrup and Butte, 2001; Sheldon et al., 1993). In infants and toddlers, polymer toys softened with phthalates were suspected as a potential source of phthalate exposure via mouthing activities. Estimates of DINP exposures ranged from 5 to 44 mg/kg bodyweight/day, with 99th percentiles up to 183 mg/kg bodyweight/day (Kavlock et al., 2002). For DEHP the calculation of exposure of children sucking or chewing toys or other articles of everyday use reached up to 85 mg/kg bodyweight/day (ATSDR, 2002). Considering the assumed toxicity of phthalates and the release rate from toys, the use of DnBP, BBzP, DEHP, DINP, and DIDP in toys intended for consumers younger than 3 years was prohibited in the EU in 1999 (COM, 1999). Whereas the use of consumer products and various other indoor sources are mainly responsible for the exposure to dimethyl, diethyl, dibutyl, benzylbutyl, diisononyl, and diisodecyl phthalate, foodstuffs represent the main exposure source for diisobutyl, dibutyl, and di-2-ethylhexyl phthalate (Wormuth et al., 2006; Schettler, 2006).
Exposure assessment by modelling ambient exposure data Based on those ambient monitoring data, exposure of the consumers has been estimated. The primary exposure to phthalates is from ingestion of foods, especially fatty foods such as milk, butter, and meats, but low-molecular weight phthalates (DEP, DBP, BBzP) may also be dermally absorbed, and the more volatile phthalates can be absorbed by inhalation (ATSDR, 1995, 2000). The exposure assessments of the NTPCERHR were: DBP 2–10 mg/kg bodyweight/day, DnOP and DIDP 530 mg/kg bodyweight/day and DEHP up to 30 mg kg bodyweight/day (NTP-CERHR, 2000, 2003a–f). Generally, the exposure of children to phthalates exceeds that in adults. Estimations of the daily intake of DEHP in the population of Canada in the early 1990s resulted in 9 mg/kg bodyweight/day for infants, 19 mg/kg bodyweight/day for toddlers, 14 mg/kg bodyweight/day in children and 6 mg/kg bodyweight in adults (Meek and Chan, 1994). A more detailed exposure assessment for European consumers according to scenario-based risk assessment approach (SceBRA) was recently published (Wormuth et al., 2006). Analyses of oral, dermal and inhalation pathways causing consumer exposure in Europe to eight different phthalates in the age groups infants, toddlers, children, teens and adults were done. Again, infants and
627
toddlers experienced higher daily exposure to all the phthalates investigated than teens or adults. In infants and toddlers, mean daily exposure to DINP and DIDP even was calculated to be higher than the maximum exposure to these phthalates in all other age groups investigated. Their maximum exposure to DEHP and DINP was higher than 100 mg/kg bodyweight/day, mainly by mouthing of soft plastic toys and the ingestion of food and dust. Obviously, the TDI for DEHP was exceeded and the range of the TDI for DINP was reached in a considerable percentage of infants (Table 4). Regarding the contribution of various sources to exposure in the different consumer groups, consistent patterns could be found for four of the eight phthalates: indoor air caused most of the exposure to DMP, the usage of personal care products such as skin care products, shampoos, etc., was predominant in the exposure to DEP, and food was the dominating source of exposure to DBP and DEHP (495%) – however, in infants and toddlers a certain amount of exposure to DBP and DEHP was caused by ingestion of dust or by mouthing as well (o20–30%). Concerning BBzP, DINP, and DIDP, sources of exposure varied extremely between infants/toddlers and adults: mouthing and ingestion of dust was found to be the main exposure source in infants/toddlers (475% BBzP, 495% DINP, DIDP), a source neglectible in adults (Wormuth et al., 2006).
Exposure assessment by human biomonitoring Another method of exposure assessment is to measure internal exposure, i.e. via analysis of the specific metabolites in urine. The relatively polar and lowmolecular-weight phthalates (e.g., DBP) primarily metabolize to their monoesters and are excreted (Albro and Moore, 1974; ATSDR, 1995, 2001), whereas the highermolecular-weight phthalates (e.g. DEHP, DnOP, DINP) are hydrolysed to their respective monoesters first, which, in a multistep pathway are metabolized to more hydrophilic oxidative metabolites (Albro et al., 1974). Major DEHP-metabolites known are: mono-(-2ethyl-5hexyl)phthalate (MEHP), mono-(-2ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono-(-2ethyl-5-oxohexyl) phthalate (5oxo-MEHP), mono-(-2ethyl-5-carboxypentyl) phthalate (5cx-MEPP), mono-[-2(carboxymethyl)hexyl] phthalate (2cx-MMHP); fast and reliable analytical methods for these compounds were developed recently (Koch et al., 2003a, 2005a; Silva et al., 2006a, b; Kato et al., 2003, 2004; Preuss et al., 2005). In consequence of the ubiquitous use and contamination with phthalates, phthalate metabolites can be detected in urine samples of the general population. Most of the published data have been obtained from
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2.68 50.94 1.61 18.57 1.89 16.32 0.29 0.09 92.38 0.22 1.15 0.45 3.61 0.31 2.85 0.00 0.00 8.59 2.54 64.93 1.45 38.56 1.65 14.71 0.26 0.08 124.17 0.22 1.43 0.41 3.53 0.27 2.54 0.00 0.00 8.42 6.28 4.44 1.25 17.01 1.24 17.44 5.61 0.47 53.73 0.49 0.76 0.29 1.23 0.06 1.97 0.19 0.03 5.00 9.72 8.31 2.62 25.42 3.67 62.10 67.19 4.24 183.28 0.76 1.49 0.68 2.55 0.31 6.31 7.07 0.51 19.68 23.46 19.74 5.58 44.92 7.56 135.28 135.02 8.99 380.57 1.81 3.48 1.57 7.60 0.76 16.16 21.98 1.43 54.80 DMP DEP DBP DnBP BBzP DEHP DINP DIDP Mean
Maximum (mg/ kg bw day) Mean (mg/ kg bw day) Maximum (mg/ kg bw day) Mean (mg/ kg bw day) Maximum (mg/ kg bw day) Mean (mg/ kg bw day) Maximum (mg/ kg bw day) Mean (mg/ kg bw day) Maximum (mg/ kg bw day) Mean (mg/ kg bw day)
Phthalate Infants 0–12 mo (5.5 kg bw)
Toddlers 1–3 years (13 kg bw)
Children 4–10 years (27 kg bw) Female adults 18–80 years (60 kg bw)
Male adults 18–80 years (70 kg bw)
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Table 4. Daily internal exposure to eight phthalates (in mg/kg bodyweight day) in 5 consumer groups, mean and maximal exposure – estimations based on ambient monitoring and scenario calculations for uptake of food, air, water, consumer products, household dust, leaching from toys, etc. (Wormuth et al., 2006)
628
studies in Germany and the USA (Becker et al., 2004; Koch et al., 2003b, 2004a, b, 2005a–c, 2006; Kato et al., 2004; Silva et al., 2004; CDC, 2005) (Table 4). In the NHANES Study 1999–2000 children had higher levels of MBP, MBzP and MEHP, but had significant lower levels of MEP. Females had significantly higher levels of MEP and MBzP (monobenzyl phthalate) than men, but similar MEHP levels (Silva et al., 2004). The high levels of MEP were most likely associated with the everyday use of consumer products, that commonly contain DEP. Adults are more likely to use cosmetics than children; these data are consistent with the recent exposure assessment via ambient monitoring for Europeans (Wormuth et al., 2006). Compared to the NHANES data 1988–1994, a decrease in the metabolite levels MEP, MBP, MBzP and MEHP could be found (Barr et al., 2003) (Table 5). Because of the complex metabolization of DEHP, intake estimations solely based on the biomarker MEHP have drawbacks. MEHP is also formed out of DEHP by abiotic processes and therefore is an environmental contaminant of its own. Hence, MEHP cannot unambiguously discriminate between exposure and secondary cross contamination during sample handling and processing. Furthermore, the metabolite MEHP represents only less than 10% of the original DEHP dose, and it has the shortest half-life of elimination of the metabolites to be investigated. Recently, a study of the elimination characteristics of DEHP showed, that the major share of the metabolites excreted in urine after exposure to DEHP are the secondary metabolites. After 24 h, 67% of the DEHP dose was excreted in urine as five of the major metabolites 5-OH-MEHP (23.3%), 5cx-MEPP (18.5%), 5oxo-MEHP (15.0%), MEHP (5.9%) and 2cx-MMHP (4.2%). The oxidized DEHP metabolites exhibit considerably longer half-lives of elimination than the monoester MEHP: MEHP 5 h, 5OH-MEHP and 5oxo-MEHP 10 h, 5cx-MEPP 12–15 h and 2cx-MMHP 24 h (Koch et al., 2005a, 2006; Preuss et al., 2005). The long half-life of elimination makes 5cxMEPP and 2cx-MMHP excellent parameters to measure the time-weighted body burden to DEHP (Koch et al., 2006). 5-OH-MEHP and 5oxo-MEHP more reflect the short-term exposure (Koch et al., 2005a; Preuss et al., 2005). Furthermore, there are strong hints that the secondary oxydized DEHP metabolites, not DEHP or MEHP, are the ultimate developmental toxicants (Regnier et al., 2004; Stroheker et al., 2005). Therefore, the secondary oxidized DEHP metabolites are considered excellent and robust parameters for DEHP biomonitoring (Koch et al., 2006). With these analytical methods available, several studies in Germany as well as in the USA have been published using these parameters up to now (Table 6). Given the urinary levels of the secondary metabolites of DEHP and the ratio of these metabolites in urine,
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Table 5.
Monoester metabolite levels of phthalates in population samples from USA and Germany (mg/l)
Study, author
Year
NHANES, Blount et al. (2000) CDC (2003) NHANES Silva et al. (2004) Duty et al. (2005) Koch et al. (2003a, b) Koch et al. (2004a, b, 2005a–c)
1988–1994 1999–2000
1999–2003 2002 2003
n
Age (yr)
MEP median (P95)
MBP median (P95)
MBZP median (P95)
MEHP median (P95)
289
20–60
305.0 (3750)
41.0 (294)
21.2 (137)
2.7 (21.5)
328 753 1456 141 85 36
6–11 12–19 420 20–54 7–65 2.6–6.5
74.7 (756) 193.0 (3260) 180.0 (3480) 160.0 (2103) 90.2 (560.5) n.a.
40.0 (163) 36.1 (165) 23.0 (142) 16.2 (69.9) 181.2 (824.9) 139.0 (3058 max) 91.8 (184 max)
40.3 (214) 28.3 (125) 13.8 (86.3) 7.9 (38.4) 21.0 (145.7) 22.1 (164 max) 12.7 (39.4 max)
4.9 (34.5) 3.7 (22.8) 3.0 (22.4) 6.3 (112.0) 10.3 (37.9) 6.6 (14.6)
19
Table 6.
629
20–59
9.0 (29.0)
Mean body burden to DEHP, expressed in the urinary excretion of DEHP metabolites (in mg/l)
Author, year Population Koch et al., 2003a, b Barr et al., 2003 Becker et al., 2004 Kato et al., 2004 Preuss et al., 2005 Silva et al., 2006a, b CDC, 2005
Population
Year
Germany, random US, random Germany, pilot US, random
2002
2002
Germany, random USA
2005 2003–2004
USA
2001–2002
Special risk groups Koch et al., Germany 2005a–c Germany Koch et al., 2006 Calafat et al., 2004
USA
Number
Age
MEHP
5OHMEHP
5oxoMEHP
5cxMEPP
2cxMMHP
85
7–63
10.3
46.8
36.5
n.a
n.a.
62 254
3–14
4.5 7.2
35.9 52.1
28.3 41.4
n.a n.a
n.a. n.a.
oLOD
17.4
15.6
n.a
n.a.
Children, adults Adults (median) 6–11 years (geo mean) 12–19 years (geo mean) 420 years (geo mean)
9.8
47.5
39.7
85.5
36.6
3.1
15.3
7.1
15.6
5.9
4.40
33.6
23.34
n.a.
n.a.
4.57
24.9
17.5
4.20
18.1
12.0
Adult platelet donors Neonatal patients (25–40 week) Neonatal care patients
257
926
774
n.a.
n.a.
#
557*
406*
5 550*
129*
94.4
2 399
79.1
10 228
62.2
127 19 129
2004
18
2005
42
2003–2004
6
n.a., not analysed; #, dismissed, because external contamination could not be excluded; *P95.
internal exposure to DEHP can be calculated. Daily intake can be obtained by the formula: DI½mg=kg bw=day ¼
UE½mg=gCE½mg=kg bw=day MWD , F UE 1000½mg=g MWM
where DI is the daily intake; UE the urinary excretion (of the metabolite); CE the creatinin excretion normalized by body weight; FUE the ratio of urinary excretion to total elimination; MWD the molecular weight of diester; MWM the molecular weight of metabolite.
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In effect, intake of DEHP is higher in children than in adults. The TDI is exceeded to a considerable degree, in some instances up to 20-fold, and gives reason for concern (Becker et al., 2004; Koch et al., 2003b, 2006). Exposure assessment via humanbiomonitoring results in higher internal exposure values than via modelling ambient data, especially in children (Wormuth et al., 2006).
Special problems in risk groups – exposure via medical devices and medications Medical devices containing di-(2-ethylhexyl) phthalate are a source of significant exposure in a susceptible subpopulation of individuals, especially those undergoing intensive care, platelet transfusion, hemodialysis and extracorporal membrane oxygenation (ECMO) in newborns (Schettler, 2006). Using heparinized PVC/ DEHP tubing, DEHP exposure from ECMO could be reduced considerably (Karle et al., 1997). Nevertheless exposure assessment via modelling resulted in very high levels of exposure of persons medically treated with PVC tubing; with the highest exposures in newborns undergoing ECMO (410 mg/kg bodyweight/day) (Table 7). These calculations could be confirmed by human biomonitoring studies in recent years, showing very high metabolite levels after platelet transfusion as well as in newborns undergoing intensive care therapy, etc. (Koch et al., 2005b, c; Silva et al., 2006a) (Table 6). Therefore, exposure to DEHP via medical devices, especially exposures of intensively treated infants or children can approach toxic doses in rodents, which
Table 7. Intravenous exposure to DEHP from selected medical procedures using medical devices of PVC containing DEHP (modified from US FDA, 2002) Adult DEHP (mg/kg bw day) Crystalloid i.v. solutions Total parenteral nutrition Without added lipid With added lipid Blood transfusion Trauma patient Transfusion/ ECMO Exchange transfusion Replacement transfusion
Neonate DEHP (mg/kg bw day)
0.005
0.03
0.03
0.03
0.13
2.5
8.5 3.0
14.0 22.6 0.3
leads to great concern (NTP-CERHR, 2000). Risk assessments were published by Latini et al. (2004) and Tickner et al. (2001), but also by institutions such as US FDA (2002), Health Canada (2002), and the European Commission (2002). As a result, there are no indications that neonates of high DEHP exposure have any altered long-term fertility patterns. An evaluation of adolescents exposed to significant quantities of DEHP as neonates via ECMO showed no significant adverse effects on their physical growth and pubertal maturity: thyroid, liver, renal, and male and female gonadal functions tested were within normal range for age and sex distribution (Rais-Bahrami et al., 2004). This does not prove, of course, that there is no risk. At present there is no evidence that recipients of repeated blood transfusions experience DEHP-related adverse effects (EU, 2002). In any consideration of restrictions on the use of PVC materials in medical devices, full account must be taken of the actual benefits of these materials and the balance between these benefits and risks (EU, 2002). The most detailed recommendations have been published by Health Canada (2002) (i.e. alternative products such as heparin-coated tubes should be used for all ECMO procedures in neonates and infants), tubing and storage bags used for the administration of lipophilic drugs that contain surfactants should not contain DEHP, and total parenteral nutrition (TPN) solutions should be administered to newborns and infants only via products that do not contain DEHP. Furthermore, research into further methods for reducing the release of DEHP from medical products should be urgently encouraged (Health Canada, 2002). Another potential source of exposure is medication. The need for site-specific dosage medications has led to the use of enteric coatings that allow the release of the active ingredients into the small intestine or in the colon. The enteric coatings generally consist of various polymers that contain plasticizers, including phthalates such as diethyl phthalate (DEP) and dibutyl phthalate (DBP) (Hauser et al., 2004). These substances are approved as inert ingredients in medications (US FDA, 2000, 2003). In a 30-year-old male with a medical history of ulcerative colitis and taking of Asacol–antiinflammatory remedy mesalamin as a delayed release tablet – urinary levels of MEP and MBP, the mono esters of DEP and DBP, were more than two orders of magnitude higher than the 95th percentile for males reported in the National Health and Nutrition Examination Survey (NHANES) (Hauser et al., 2004). DBP may also be an ingredient in cellulose acetate free films for transdermal use (Rao and Diwan, 1997). DBP is currently used in 64 pharmaceutical products in Germany, among others in common bronchiolytics for children and adults. In one out of 36 nursery school children studied for internal exposure to DBP and DBzP a urinary level of 2249 mg MBP/g creatinine could be
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found, caused by medication. This maximum concentration was approximately 15 times higher than that for the adults tested (Koch et al., 2005d). Intake of four tablets of a DBP-containing drug (which can be bought without prescription) by a male volunteer led to an internal exposure of 402 mg DBP/kg bodyweight, thus exceeding 4-fold the TDI value for adult women (Koch et al., 2005e). Therefore, the use of pharmaceutical drugs containing DBP should be omitted whenever possible in children and in women capable of childbearing for preventive reasons (Koch et al., 2005e).
Conclusion Phthalates are used worldwide as plasticizers in PVC materials. Many consumer products contain specific representatives of this family, resulting in ubiquitous exposure of the population. Though foodstuffs are regarded as the relevant source of exposure to the general population, in special risks groups other sources such as medical devices may be predominant. Especially in children, TDI is exceeded to a considerable degree. High exposures to phthalates can occur via medical treatment, i.e. via use of medical devices containing DEHP or pharmaceutical drugs containing DBP phthalate in their coating. Because of their chemical properties, exposure to phthalates does not result in bioaccumulation. However, health concern regarding the developmental and/or reproductive toxicity of phthalates can be raised not only on the basis of results of animal experiments but also under consideration of recently published human studies (Duty et al., 2005; Swan et al., 2005; Marsee et al., 2006), even in ambient concentrations. Further studies are necessary to shed light on possible mechanisms of action of developmental and/or reproductive effects caused by phthalates in humans.
Note added in proof After the manuscript had been finished, new data human biomonitoring of phthalates have been published in addition to those cites in the text: Fromme et al., 2007; Wittassek et al., 2007a,b.
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