Biomonitoring Summary

Phthalates Overview

Phthalates are industrial chemicals that are added to plastics to impart flexibility and resilience and are often referred to as plasticizers. Phthalates also are used as solubilizing or stabilizing agents in other applications. There are numerous products that may contain phthalates: adhesives; automotive plastics; detergents; lubricating oils; some medical devices and pharmaceuticals; plastic raincoats; solvents; vinyl tiles and flooring; and personal-care products, such as soap, shampoo, deodorants, lotions, fragrances, hair spray, and nail polish. Phthalates are often used in polyvinyl chloride type plastics, such as plastic packaging film and sheet, garden hoses, inflatable recreational toys, blood product storage bags, intravenous medical tubing, and toys (ATSDR, 2001, 2002). Because they are not chemically bound to the plastics to which they are added, phthalates can be released into the environment during use or disposal of the product. Various phthalate esters have been measured in specific foods, indoor and ambient air, indoor dust, water sources, and sediments (Clark et al., 2003).

People are exposed through ingestion, inhalation, and, to a lesser extent, dermal contact with products that contain phthalates. For the general population, dietary sources have been considered as the major exposure route, followed by inhaling indoor air. Infants may have relatively greater exposures from ingesting indoor dust containing some phthalates (Clark et al., 2003). Human milk can be a source of phthalate exposure for nursing infants (Calafat et al., 2004; Mortensen et al., 2005). The intravenous or parenteral exposure route can be important in patients undergoing medical procedures involving devices or materials containing phthalates. In settings where workers may be exposed to higher air phthalate concentrations than the general population, urinary metabolite and air phthalate concentrations are roughly correlated (Liss et al., 1985; Nielsen et al., 1985; Pan et al., 2006).

Phthalates are metabolized and excreted quickly and do not accumulate in the body (Anderson et al., 2001). Ingested phthalate diesters are initially hydrolyzed in the intestine to the corresponding monoesters, which are then absorbed (Albro et al., 1982; Albro and Lavenhar, 1989). Absorbed monoester metabolites are usually oxidized in the body and, in humans, excreted in urine largely as glucuronide conjugates (Albro et al., 1982; Dirven et al,. 1993). The table shows the phthalate diesters, corresponding monoester metabolites, and other oxidized metabolites included in the National Report on Human Exposure to Environmental Chemicals (CDC, 2013).

Human health effects from phthalates at low environmental doses or at biomonitored levels from low environmental exposures are unknown. Phthalates have low acute animal toxicity. In chronic rodent studies, several of the phthalates produced testicular injury, liver injury, liver cancer, and teratogenicity, but these effects either have not been demonstrated when tested in non-human primates or are yet to be studied. In vitro studies showed that certain phthalates can bind to estrogen receptors and may have weak estrogenic or anti-estrogenic activity (Coldham et al., 1997; Harris et al., 1997; Jobling et al., 1995), but in vivo studies did not support phthalates having estrogenic effects (Milligan et al., 1998; Okubo et al., 2003; Parks et al., 2000; Zacharewski et al., 1998); however, not all phthalates and metabolites have been tested. In animals, phthalates produced anti-androgenic effects by reducing testosterone production and, at very high levels, reducing estrogen production, effects that may be mediated by inhibiting testicular and ovarian steroidogenesis. High doses of di-2-ethylhexyl phthalate (DEHP), dibutyl phthalate (DBP), and benzylbutyl phthalate (BzBP) during the fetal period produced lowered testosterone levels, testicular atrophy, and Sertoli cell abnormalities in the male animals and, at higher doses, ovarian abnormalities in the female animals (Jarfelt et al., 2005; Lovekamp-Swan and Davis, 2003; McKee et al., 2004; NTP-CERHR, 2003a, 2003b, 2006). Phthalate urinary metabolite levels in men evaluated at an infertility clinic were associated with several measures of sperm function and morphology (Duty et al., 2004; Hauser et al., 2007), but similar findings were not present in young Swedish men with comparable or higher median levels of urinary metabolites (Jonsson et al., 2005).

The monoester metabolites are thought to mediate toxic effects for some of the phthalates, but there are known species-related differences in the hydrolysis of diester phthalates, efficiency of intestinal absorption, and extent of metabolite conjugation to glucuronide (Albro et al., 1982; Kessler et al., 2004; Rhodes et al., 1986). These differences may contribute to species-specific differences in toxicity (ATSDR, 2001, 2002). Also, phthalates have been shown to induce peroxisomal proliferation in rodents, which may be a pathway to the development of liver toxicity and cancers in these animals. However, peroxisomal proliferation may not be a relevant pathway in humans (Rusyn et al., 2006).

The National Toxicology Program's Office of Health Assessment and Translation, formerly Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) has reviewed the developmental and reproductive effects of specific phthalates (https://www.niehs.nih.gov/research/atniehs/dntp/ohat/index.cfmexternal icon). Information about external exposure (i.e., environmental levels) and health effects is also available for some phthalates from ATSDR at https://www.atsdr.cdc.gov/toxprofiles/index.asp.

Phthalates and Urinary Metabolites Measured in the National Biomonitoring Program

Table of Phthalates and Urinary Metabolites Measured in the National Biomonitoring Program
Phthalate name (CAS number)	Abbreviation	Urinary metabolite (CAS number)	Abbreviation
Benzylbutyl phthalate (85-68-7)	BzBP	Mono-benzyl phthalate (2528-16-7) (some mono-n-butyl phthalate)	MBzP
Dibutyl phthalates (84-74-2)	DBP	Mono-n-butyl phthalate (131-70-4) Mono-isobutyl phthalate	MnBP MiBP
Dicyclohexyl phthalate (84-61-7)	DCHP	Mono-cyclohexyl phthalate (7517-36-4)	MCHP
Diethyl phthalate (84-66-2)	DEP	Mono-ethyl phthalate (2306-33-4)	MEP
Di-2-ethylhexyl phthalate (117-81-7)	DEHP	Mono-2-ethylhexyl phthalate (4376-20-9) Mono-(2-ethyl-5-hydroxyhexyl) phthalate Mono-(2-ethyl-5-oxohexyl) phthalate Mono-(2-ethyl-5-carboxypentyl) phthalate (40809-41-4)	MEHP MEHHP MEOHP MECPP
Di-isononyl phthalate (28553-12-0)	DiNP	Mono-isononyl phthalate	MiNP
Di-isodecyl phthalate	DiDP	Mono-(carboxynonyl) phthalate	MCNP
Dimethyl phthalate (131-11-3)	DMP	Mono-methyl phthalate (4376-18-5)	MMP
Di-n-octyl phthalate (117-84-0)	DOP	Mono-(3-carboxypropyl) phthalate Mono-n-octyl phthalate (5393-19-1)	MCPP MOP

Urinary levels of phthalate metabolites reflect recent exposure to the parent phthalate diester. The proportions of each metabolite for a given phthalate may vary by differing routes of exposure (Liss et al., 1985; Peck and Albro, 1982). Variation occurs from person to person in the proportions or amounts of a metabolite excreted after similar doses (Anderson et al., 2001); variation also occurs in the same person during repetitive monitoring (Fromme et al., 2007; Hauser et al., 2004; Hoppin et al., 2002). Population estimates of concentrations of specific phthalate metabolites may differ by age, gender, and race/ethnicity (Silva et al., 2004).

Finding a measurable amount of one or more phthalate metabolites in urine does not imply that the levels of the metabolites or the parent phthalate cause an adverse health effect. Biomonitoring studies on levels of phthalate metabolites provide physicians and public health officials with reference values so that they can determine whether people have been exposed to higher levels of phthalates than are found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects.

Di-isobutyl Phthalate

CAS No. 84-69-5

General Information

Dibutyl phthalates (both di-n-butyl and di-isobutyl phthalates, referred to as DBP) are industrial solvents or additives used in many personal care products such as nail polish and cosmetics, and also in some printing inks, pharmaceutical coatings, and insecticides. People exposed to dibutyl phthalates will excrete mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) in their urine. When total DBP metabolites have been measured, they have been referred to as monobutyl phthalate (MBP). Small amounts of mono-3-carboxypropyl phthalate are also produced from di-n-butyl phthalate. In addition, exposure to benzylbutyl phthalate (BzBP) will also result in small amounts of mono-n-butyl phthalate appearing in the urine. Following oral administration of DBP to humans, about 65% to 80% of a dose is eliminated in urine within 24 hours, mostly as MnBP (Anderson et al., 2001). DBP can produce reproductive toxicity in male rodents (McKee et al., 2004; NTP-CERHR, 2000). OSHA has established a workplace air standard for external exposure to DBP; NIOSH and ACGIH have established guidelines for workplace air exposure to di-n-butyl phthalate. Neither IARC nor NTP has evaluated dibutyl phthalates with respect to human carcinogenicity.

Biomonitoring Information

Median concentrations reported in the NHANES 1999-2000, 2001-2002 and 2003-2004 subsamples were similar to MBP levels reported in U.S. residents (Blount et al., 2000), in men attending a Boston infertility clinic (Duty et al., 2004; Hauser et al., 2007), in a small sample of pregnant women in New York City (Adibi et al., 2003), and in a small sample of Japanese adults (Itoh et al., 2005). Median MBP levels in two European studies were about two to six times higher than median levels in the National Report on Human Exposure to Environmental Chemicals (CDC, 2013; Jonsson et al., 2005; Koch et al., 2003). Studies of children found age-related differences in urine MBP levels. Compared with the median for 6 to 11 year olds in NHANES 1999-2004 (CDC, 2013), the median for neonates was lower (by about half) and the median for toddlers was higher (by about sixfold) (Brock et al., 2002; Weuve et al., 2006). In an analysis of NHANES 1999-2000, the adjusted geometric mean levels of urinary MBP were significantly higher in children aged 6 to 11 years than in either adolescents or adults (Silva et al., 2004). Differences in urinary MBP population estimates by gender have also been shown (Silva et al., 2004). An analysis of NHANES 2001-2002 showed similar age- and gender- related differences in the adjusted geometric mean levels of urinary MiBP and MnBP (CDC, 2013).

Studies measuring urinary MnBP have reported variable median values compared to the NHANES 2001-2002 and 2003-2004 subsamples, ranging from more than one-tenth the NHANES median (Itoh et al, 2005), to about two to fourfold higher (Fromme et al., 2007). Between 1998 and 2003, samples from German university students had consistently higher median urine levels of MnBP and MiBP, up to four and 13 fold, respectively, than adults in NHANES subsamples during the same time period (CDC, 2012). Over this time, the students’ median values for MiBP levels remained relatively unchanged, while MnBP declined (Wittassek et al., 2007).

Finding a measurable amount of MnBP or MiBP in urine does not imply that these levels or the parent compound cause an adverse health effect. Biomonitoring studies on levels of MnBP and MiBP provide physicians and public health officials with reference values so that they can determine whether people have been exposed to higher levels of dibutyl phthalates than are found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects.

References

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