Protecting Public Health from Phthalates Will Require Consideration of Cumulative Risks
Statement of Olga Naidenko, Ph.D., Senior Scientist
Environmental Working Group
To the National Research Council
Meeting 2 – Committee on the Health Risks of Phthalates
February 21, 2008
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Thank you for this new opportunity to present the views of the Environmental Working Group (EWG) on the urgent need for a cumulative human health risk assessment for phthalates. EWG is a non-profit health and environmental research and advocacy organization based in Washington DC. For the past seven years we have been conducting our own studies on phthalates that include biomonitoring and product research. In addressing this Committee on the first meeting in December, we argued that a rapidly expanding body of research points to the need for a cumulative risk assessment for phthalates. Such as assessment is essential to protect public health, especially the health of baby boys, the population most vulnerable to phthalates (Frederiksen 2007; Jarosinska 2007; Swan 2006).
A cumulative risk assessment for phthalates is both necessary to protect human health and feasible based on our review of the scientific literature:
- People are exposed to many phthalates at any given time. 84% of the U.S. population is contaminated with at least six different phthalates at any given time, according to EWG’s analysis of biomonitoring data from the Centers for Disease Control and Prevention (CDC) (CDC 2005). EPA’s current practice is to set health standards (reference doses, or RfD’s) for phthalates based on an implicit assumption that people are exposed to just one phthalate at a time. This assumption is false and results in health standards that may not adequately protect health of the vulnerable populations.
- Studies show that phthalates cause harm via a common mechanism of action, and that their impacts to health would be additive. Studies from different laboratories indicate that phthalates disrupt male sexual differentiation and produce adverse reproductive effects by the same mechanism of action that targets the steroid hormone synthesis pathway (Clark 2007; Hallmark 2007; Howdeshell 2007; Hutchison 2008; Supornsilchai 2007; Svechnikova 2007). The fact that these chemicals do not act independently of each other points to the need for dose additive risk assessment (Sexton 2007).
- Studies of health effects in people also find impacts linked to multiple phthalates, supporting data that indicates a common mechanism of action. Epidemiology studies consistently linked multiple phthalates to a broad range of health effects, starting with birth defects in baby boys and reproductive problems in men, and extending to thyroid and immune disruption (Heudorf 2007; Wormuth 2006).
- Methods are available to conduct a cumulative risk assessment for phthalates. EPA has already established methods for cumulative risk assessments beginning about 20 years ago with their assessment of dioxin (U.S. EPA 2004). Congress mandated the assessment of cumulative risks for pesticides in food with the passage of the Food Quality Protection Act in 1996. Development of appropriate weighting factors or toxic equivalency factors to account for differing potencies of individual phthalates will facilitate the application of cumulative risk assessment for this family of chemicals (DiGangi 2002; Sexton 2007)
Both EPA and Congress repeatedly emphasized the importance of moving from individual risk assessments for single contaminants or chemicals to analyzing and safeguarding against combined risks due to simultaneous exposure to chemical mixtures (Callahan 2007; Gilman 2003; U.S. EPA 1997, 2000, 2003). The stage is now set and the methods are in place for a thorough review of phthalates by the EPA (Kortenkamp 2008; Wittassek and Angerer 2007).
Over the past eight years a series of scientific studies unambiguously demonstrated that the U.S. population faces chronic exposures to numerous phthalates (DiGangi 2002; Schettler 2006). Over that same period epidemiology studies consistently linked these chemicals to birth defects in baby boys, reproductive problems in men, and thyroid problems in both men and women (Duty 2005; Duty 2003; Hauser 2006; Hauser, Meeker 2007; Huang 2007; Lottrup 2006; Marsee 2006; Meeker 2007; Stahlhut 2007; Swan 2005). Furthermore, immune system effects of phthalates have also been suggested, which could be associated with illnesses such as allergy, asthma, and contact dermatitis (Bornehag 2004; Takano 2006; Wormuth 2006), all of which are on the rise in children.
This human health evidence joins dozens of laboratory studies proving phthalates to be reproductive toxicants with potent anti-androgenic effects that target nearly every aspect of male reproductive system development (Frederiksen 2007; Gray 2006; Matsumoto 2008). All of this research clearly and undeniably points in a single direction: EPA’s review of the cumulative risks of phthalates is urgently needed to ensure adequate protection of public health. Key reasons for conducting such a cumulative risk assessment are detailed below.
Exposure to multiple phthalates is ubiquitous and virtually unavoidable. Only a cumulative human health risk assessment can account for the constant exposure of the public to complex mixtures of phthalates (Calafat 2006; Howdeshell 2007; Rider 2008; Silva, Barr 2004; Wittassek and Angerer 2007; Wittassek, Wiesmuller 2007). Reports of research groups all over the world indicate that most industrial consumer products contain phthalates or traces of phthalates (Frederiksen 2007; Sathyanarayana 2008; Schettler 2006). People are exposed to phthalates through all imaginable routes: by ingestion, inhalation, dermal absorption, and even by direct intravenous transfer from medical devices (Heudorf 2007)! Scientists at the Centers for Disease Control and Prevention (CDC) detected phthalates in urine samples from all but 12 of 2,790 people tested (CDC (Centers for Disease Control and Prevention) 2005) with six or more phthalates found in 84% of people tested.
Cumulative risk assessment is especially important for endocrine disruptors such as phthalates. Phthalates have long been known to be toxic to the male reproductive system of test animals. A series of studies published over the last several years link this family of chemicals to reproductive damage in baby boys and adult men (Hauser 2007; Hauser 2006; Lottrup 2006; Main 2006; Marsee 2006; Sharpe 2005; Swan 2005). Exposure to phthalates affects levels of various hormones, which include reproductive hormones such as testosterone, luteinizing hormone, and follicle-stimulating hormone (Main 2006) as well as thyroid hormones (Huang 2007; Meeker 2007), which confirms the endocrine disrupting properties of these chemicals (Kortenkamp 2008).
Baby boys and pregnant women are two groups especially vulnerable to hormone-disrupting effects of phthalates. Alarmingly, these are precisely the groups whose high level exposure to multiple phthalates has been extensively documented (Adibi 2008; Sathyanarayana 2008; Silva, Barr 2004). Phthalates cross the placenta into amniotic fluid (Silva, Reidy 2004); they are also transferred from the mother to the infant with breast milk (Main 2006). A child’s exposure to these potent anti-androgenic chemicals starts from the prenatal stage and continues through the formative early years. As a result, the exposure of children to phthalates generally exceeds that of adults (Heudorf 2007). Infants, with their small body size, and different behavioral patterns from adults, are most at risk from phthalates.
Hypothyroidism patients may also represent a vulnerable group at heightened risk from phthalate exposure. An estimated 8 millions of Americans suffer from underactive thyroid (Thyroid Foundation Of America 2004). Thus, thyroid patients, pregnant women, and baby boys are all groups at risk from numerous sources of endocrine-disrupting phthalates in consumer products. Only a cumulative risk assessment can adequately protect the health of these sensitive populations.
A cumulative human health risk assessment is supported by additive anti-androgenic activity of multiple phthalates. Individual risk assessments for the most common phthalates have already been carried out by the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction. Seven phthalates (butyl benzyl phthalate (BBP), di-n-butyl phthalate (DBP), di-(2-ethylhexyl) phthalate (DEHP), diisodecyl phthalate (DIDP), diisononyl phthalate (DINP), di-n-hexyl phthalate (DnHP), di-n-octyl phthalate (DINP) were selected for NTP-CERHR evaluation because of their high production volume, significant human exposures, use in children’s products, and published evidence of reproductive or developmental toxicity (NTP-CERHR 2003a, b, c, d, e, f, 2006).
Although different phthalates are processed in the human body into a broad array of distinct metabolites (Silva 2007), studies from different laboratories indicate that phthalates disrupt male sexual differentiation and produce adverse reproductive effects by the same mechanism of action that targets the steroid hormone synthesis pathway (Clark 2007; Hallmark 2007; Howdeshell 2007; Hutchison 2008; Supornsilchai 2007; Svechnikova 2007). The fact that these chemicals do not act independently of each other points to the need for dose additive risk assessment (Sexton 2007). In reality, the situation is likely to be even more complex with the human exposure to multiple anti-androgenic and endocrine disrupting chemicals (Gray 2006; Hotchkiss 2004; Kortenkamp 2008; Rider 2008). At the very least, we need to address the cumulative impact of phthalates, since newly developed methods allow scientists and risk assessors to enumerate and account for different sources of phthalate exposure (Silva 2007; Wittassek and Angerer 2007).
Ongoing biomonitoring research facilitates cumulative risk assessment for phthalates. First, current efforts on the state and federal levels promote environmental health tracking systems that combine information about sources, doses, and health effects of environmental hazards. For phthalates, collecting a comprehensive exposure dataset will represent a major breakthrough in our understanding of the potential risks of these ubiquitous chemicals. Second, large-scale prospective biomonitoring studies at the CDC already started to provide valuable data on exposure to multiple environmental agents, especially endocrine disrupting chemicals and developmental toxicants (Calafat 2006; Calafat 2007; Needham 2008). Finally, advances in biomedical sciences and a variety of innovative technologies provide new quantitative tools for assessing the effects of cumulative environmental exposure. These technologies should be harnessed to promote public health (Sexton 2007) and protect the most vulnerable populations (DeFur 2007). Using these methods, we can now assess and manage the risks posed by phthalates taking into account their multiple sources, multiple routes of exposure, and multiple toxicological end-points.
In conclusion, a national-level policy of cumulative risk assessment for phthalates will provide the necessary guidance to companies, states and consumers, allowing for case-specific responses and rectifying the current lack of regulatory oversight for this entire family of chemicals.
References
Adibi JJ, Whyatt RM, Williams PL, Calafat AM, Camann DE, Herrick R, et al. 2008. Characterization of phthalate exposure among pregnant women assessed by repeat air and urine samples. Environ Health Perspect in press.
Bornehag CG, Sundell J, Weschler CJ, Sigsgaard T, Lundgren B, Hasselgren M, et al. 2004. The association between asthma and allergic symptoms in children and phthalates in house dust: a nested case-control study. Environ Health Perspect 112(14): 1393-7.
Calafat AM, McKee RH. 2006. Integrating biomonitoring exposure data into the risk assessment process: phthalates [diethyl phthalate and di(2-ethylhexyl) phthalate] as a case study. Environ Health Perspect 114(11): 1783-9.
Calafat AM, Needham LL. 2007. Factors affecting the evaluation of biomonitoring data for human exposure assessment. Int J Androl in press.
Callahan MA, Sexton K. 2007. If cumulative risk assessment is the answer, what is the question? Environ Health Perspect 115(5): 799-806.
CDC (Centers for Disease Control and Prevention). 2005. Third National Exposure Report. Available: http://www.cdc.gov/exposurereport/report.htm [accessed February 19 2008].
Clark BJ, Cochrum RK. 2007. The steroidogenic acute regulatory protein as a target of endocrine disruption in male reproduction. Drug Metab Rev 39(2-3): 353-70.
DeFur PL, Evans GW, Cohen Hubal EA, Kyle AD, Morello-Frosch RA, Williams DR. 2007. Vulnerability as a function of individual and group resources in cumulative risk assessment. Environ Health Perspect 115(5): 817-24.
DiGangi J, Schettler T, Cobbing M, Rossi M. 2002. Aggregate Exposures to Phthalates in Humans. Washington, DC: Health Care Without Harm.
Duty SM, Calafat AM, Silva MJ, Ryan L, Hauser R. 2005. Phthalate exposure and reproductive hormones in adult men. Hum Reprod 20(3): 604-10.
Duty SM, Silva MJ, Barr DB, Brock JW, Ryan L, Chen Z, et al. 2003. Phthalate exposure and human semen parameters. Epidemiology 14(3): 269-77.
Frederiksen H, Skakkebaek NE, Andersson AM. 2007. Metabolism of phthalates in humans. Mol Nutr Food Res 51(7): 899-911.
Gilman P. 2003. EPA Framework on Cumulative Risk Assessment. Letter from Paul Gilman, EPA Science Advisor and Chair, Science Policy Council. June 25 2003. Available: http://www.epa.gov/OSA/spc/pdfs/crmemo.pdf [accessed February 19 2008].
Gray LE, Jr., Wilson VS, Stoker T, Lambright C, Furr J, Noriega N, et al. 2006. Adverse effects of environmental antiandrogens and androgens on reproductive development in mammals. Int J Androl 29(1): 96-104.
Hallmark N, Walker M, McKinnell C, Mahood IK, Scott H, Bayne R, et al. 2007. Effects of monobutyl and di(n-butyl) phthalate in vitro on steroidogenesis and Leydig cell aggregation in fetal testis explants from the rat: comparison with effects in vivo in the fetal rat and neonatal marmoset and in vitro in the human. Environ Health Perspect 115(3): 390-6.
Hauser R. 2007. Urinary phthalate metabolites and semen quality: a review of a potential biomarker of susceptibility. Int J Androl 30: 1-5.
Hauser R, Meeker JD, Duty S, Silva MJ, Calafat AM. 2006. Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiology 17(6): 682-91.
Hauser R, Meeker JD, Singh NP, Silva MJ, Ryan L, Duty S, et al. 2007. DNA damage in human sperm is related to urinary levels of phthalate monoester and oxidative metabolites. Hum Reprod 22(3): 688-95.
Heudorf U, Mersch-Sundermann V, Angerer J. 2007. Phthalates: toxicology and exposure. Int J Hyg Environ Health 210(5): 623-34.
Hotchkiss AK, Parks-Saldutti LG, Ostby JS, Lambright C, Furr J, Vandenbergh JG, et al. 2004. A mixture of the "antiandrogens" linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. Biol Reprod 71(6): 1852-61.
Howdeshell KL, Furr J, Lambright CR, Rider CV, Wilson VS, Gray LE, Jr. 2007. Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes. Toxicol Sci 99(1): 190-202.
Huang PC, Kuo PL, Guo YL, Liao PC, Lee CC. 2007. Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Hum Reprod 22(10): 2715-22.
Hutchison GR, Scott HM, Walker M, McKinnell C, Ferrara D, Mahood IK, et al. 2008. Sertoli cell development and function in an animal model of testicular dysgenesis syndrome. Biol Reprod 78(2): 352-60.
Jarosinska D, Gee D. 2007. Children's environmental health and the precautionary principle. Int J Hyg Environ Health 210(5): 541-6.
Kortenkamp A. 2008. Low dose mixture effects of endocrine disrupters: implications for risk assessment and epidemiology. Int J Androl in press.
Lottrup G, Andersson AM, Leffers H, Mortensen GK, Toppari J, Skakkebaek NE, et al. 2006. Possible impact of phthalates on infant reproductive health. Int J Androl 29(1): 172-80.
Main KM, Mortensen GK, Kaleva MM, Boisen KA, Damgaard IN, Chellakooty M, et al. 2006. Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environ Health Perspect 114(2): 270-6.
Marsee K, Woodruff TJ, Axelrad DA, Calafat AM, Swan SH. 2006. Estimated daily phthalate exposures in a population of mothers of male infants exhibiting reduced anogenital distance. Environ Health Perspect 114(6): 805-9.
Matsumoto M, Hirata-Koizumi M, Ema M. 2008. Potential adverse effects of phthalic acid esters on human health: a review of recent studies on reproduction. Regul Toxicol Pharmacol 50(1): 37-49.
Meeker JD, Calafat AM, Hauser R. 2007. Di(2-ethylhexyl) phthalate metabolites may alter thyroid hormone levels in men. Environ Health Perspect 115(7): 1029-34.
Needham LL, Calafat AM, Barr DB. 2008. Assessing developmental toxicant exposures via biomonitoring. Basic Clin Pharmacol Toxicol 102(2): 100-8.
NTP-CERHR. 2003a. NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Butyl Benzyl Phthalate (BBP).
NTP-CERHR. 2003b. NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di-Isodecyl Phthalate (DIDP).
NTP-CERHR. 2003c. NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di-isononyl Phthalate (DINP).
NTP-CERHR. 2003d. NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di-n-Butyl Phthalate (DBP).
NTP-CERHR. 2003e. NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di-n-Hexyl Phthalate (DnHP).
NTP-CERHR. 2003f. NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di-n-Octyl Phthalate (DnOP).
NTP-CERHR. 2006. NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di(2-ethylhexyl) Phthalate (DEHP).
Rider CV, Furr J, Wilson VS, Gray LE, Jr. 2008. A mixture of seven antiandrogens induces reproductive malformations in rats. Int J Androl in press.
Sathyanarayana S, Karr CJ, Lozano P, Brown E, Calafat AM, Liu F, et al. 2008. Baby care products: possible sources of infant phthalate exposure. Pediatrics 121(2): e260-8.
Schettler T. 2006. Human exposure to phthalates via consumer products. Int J Androl 29(1): 134-9.
Sexton K, Hattis D. 2007. Assessing cumulative health risks from exposure to environmental mixtures - three fundamental questions. Environ Health Perspect 115(5): 825-32.
Sharpe RM. 2005. Phthalate exposure during pregnancy and lower anogenital index in boys: wider implications for the general population? Environ Health Perspect 113(8): A504-5.
Silva MJ, Barr DB, Reidy JA, Malek NA, Hodge CC, Caudill SP, et al. 2004. Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Environ Health Perspect 112(3): 331-8.
Silva MJ, Reidy JA, Herbert AR, Preau JL, Jr., Needham LL, Calafat AM. 2004. Detection of phthalate metabolites in human amniotic fluid. Bull Environ Contam Toxicol 72(6): 1226-31.
Silva MJ, Samandar E, Preau JL, Jr., Reidy JA, Needham LL, Calafat AM. 2007. Quantification of 22 phthalate metabolites in human urine. J Chromatogr B Analyt Technol Biomed Life Sci 860(1): 106-12.
Stahlhut RW, van Wijngaarden E, Dye TD, Cook S, Swan SH. 2007. Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environ Health Perspect 115(6): 876-82.
Supornsilchai V, Soder O, Svechnikov K. 2007. Stimulation of the pituitary-adrenal axis and of adrenocortical steroidogenesis ex vivo by administration of di-2-ethylhexyl phthalate to prepubertal male rats. J Endocrinol 192(1): 33-9.
Svechnikova I, Svechnikov K, Soder O. 2007. The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats. J Endocrinol 194(3): 603-9.
Swan SH. 2006. Does our environment affect our fertility? Some examples to help reframe the question. Semin Reprod Med 24(3): 142-6.
Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, et al. 2005. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 113(8): 1056-61.
Takano H, Yanagisawa R, Inoue K, Ichinose T, Sadakane K, Yoshikawa T. 2006. Di-(2-ethylhexyl) phthalate enhances atopic dermatitis-like skin lesions in mice. Environ Health Perspect 114(8): 1266-9.
Thyroid Foundation Of America. 2004. The most common problem—Hypothyroidism. Available: http://www.tsh.org/disorders/hypothyroidism/hypothyroidism.html [accessed February 19 2008].
U.S. EPA. 1997. Memorandum from Administrator Carol Browner to EPA senior staff. Cumulative Risk Assessment Guidance-Phase I Planning and Scoping. Available: http://www.epa.gov/swerosps/bf/html-doc/cumulrsk.htm [accessed February 19 2008].
U.S. EPA. 2000. Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures. Available: http://www.epa.gov/NCEA/pdfs/chem_mix/chem_mix_08_2001.pdf [accessed February 19 2008].
U.S. EPA. 2003. Framework for Cumulative Risk Assessment. PA/630/P-02/001A. Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum, Office of Research and Development.
U.S. EPA. 2004. Exposure and Human Health Reassessment of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds National Academy Sciences (NAS) Review Draft. Available: http://www.epa.gov/ncea/pdfs/dioxin/nas-review/ [accessed February 19, 2008 2008].
Wittassek M, Angerer J. 2007. Phthalates: metabolism and exposure. Int J Androl 30: 1-6.
Wittassek M, Wiesmuller GA, Koch HM, Eckard R, Dobler L, Muller J, et al. 2007. Internal phthalate exposure over the last two decades--a retrospective human biomonitoring study. Int J Hyg Environ Health 210(3-4): 319-33.
Wormuth M, Scheringer M, Vollenweider M, Hungerbuhler K. 2006. What are the sources of exposure to eight frequently used phthalic acid esters in Europeans? Risk Anal 26(3): 803-24.
