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
|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)
|Dibutyl phthalates (84-74-2)||DBP||Mono-n-butyl phthalate (131-70-4)
|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-carboxypentyl) phthalate (40809-41-4)
|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)
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.
CAS No. 85-68-7
Benzylbutyl phthalate (BzBP) is a solvent and additive used in products such as adhesives, vinyl tile, sealants, car care products, and to a lesser extent, some personal care products. BzBP can be released into the environment during its production and, because it is not bound to products in which it is incorporated, it can be released into the ambient air during use or disposal of the products. Food crops take up BzBP, and diet is the major source for general population exposure. People exposed to BzBP will excrete mono-benzyl phthalate (MBzP) and small amounts of mono-n-butyl phthalate in their urine. High dose BzBP and its monoester metabolites, including MBzP, can produce developmental and reproductive toxicity in rodents, particularly male animals (McKee et al., 2004; NTP-CERHR, 2003a). IARC considers BzBP not classifiable with respect to human carcinogenicity.
The median levels of MBzP in NHANES subsamples from 1999-2000, 2001-2002, and 2003-2004 were generally similar those reportedin U.S. residents (Blount et al., 2000), in a small sample of pregnant women in New York City (Adibi et al., 2003), in men attending a Boston infertility clinic (Duty et al., 2004; Hauser et al., 2007), in young Swedish men (Jonsson et al., 2005), and in a small sample of German residents (Koch et al., 2003). In an annual sample of German university students, median urine levels of MBzP were about one half the median levels in NHANES subsamples from 1999-2002 (Wittassek et al., 2007). A small study of African-American women in Washington, DC reported median urinary MBzP levels that were about twice the levels of adults and females reported in NHANES 1999-2002 (CDC, 2012; Hoppin et al., 2002). Limited studies in children younger than 2 years old have found median and geometric mean urine MBzP that were similar to children aged 6-11 years in the NHANES subsamples (Brock et al., 2002; Weu
ve et al., 2006). In NHANES 1999-2000, the adjusted geometric mean levels of urinary MBzP were significantly higher in several subgroups: children compared to adolescents and adults; adolescents compared with adults; and females compared to males (Silva et al., 2004).
Finding a measurable amount of MBzP in the urine does not imply that the levels of MBzP or the parent compound cause an adverse health effect. Biomonitoring studies on levels of urinary MBzP provide physicians and public health officials with reference values so that they can determine whether people have been exposed to higher levels of BzBP than are found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects.
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