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1 Introduction Humans are exposed to a variety of chemicals at any one time, and the ex- posures change over time. Recognition of the dynamic and varied nature of chemical exposures has prompted a growing emphasis on assessing risks in a cumulative manner. In 1986, the U.S. Environmental Protection Agency (EPA) published Guidelines for the Health Risk Assessment of Chemical Mixtures, and over the years, the progression toward a cumulative risk paradigm has prompted the publication of several frameworks and guidance documents for conducting cumulative risk assessment (ILSI 1999; EPA 1997, 2000, 2002, 2003, 2006, 2007). Some methods have focused on structurally related chemicals on the as- sumption that they act through a common mechanism of action. Examples in- clude the development of toxic equivalency factors for dioxins (EPA 1987, 1989; Van den Berg et al. 2006) and polychlorinated biphenyls (Van den Berg et al. 2006) and the development of relative potency factors for polycyclic aro- matic hydrocarbons (EPA 1993) and cholinesterase-inhibiting organophosphate pesticides (EPA 2002). Phthalates are a group of chemicals with similar chemical structure that have been associated with effects on the development of the reproductive system of male laboratory animals. Few epidemiologic studies of phthalates and devel- opmental effects on the male reproductive system are available; however, stud- ies show widespread human exposures to phthalates. Those and other factors prompted EPA to ask that the National Research Council (NRC) assess the ap- propriateness of conducting a cumulative risk assessment of this chemical class and provide guidance for such an assessment as related not only to phthalates but to cumulative risk assessment generally. This report provides the conclu- sions and recommendations of the Committee on the Health Risks of Phthalates established by the NRC in response to EPAâs request. PHTHALATES Phthalates are diesters of benzenedicarboxylic acid. The committee re- stricted its assessment to the most biologically active phthalates, diesters of 1,2- 13
14 Phthalates and Cumulative Risk Assessment: The Tasks Ahead benzenedicarboxylic acid, or o-phthalates, which have the general chemical structure shown in Figure 1-1. Throughout this report, the term phthalates refers to the o-phthalates unless otherwise indicated. The ester side chains can vary in length and structure. For example, they can be identical as in the case of di-n-butyl phthalate (R and Râ² are both âCH2 CH2CH2CH3), or they can differ as in the case of butyl benzyl phthalate (R is âCH2CH2CH2CH3, and Râ² is âCH2C6H5). The structural differences in the ester side chains give the phthalates their individual chemical and physical properties and alter their biologic activity. Table 1-1 lists common phthalates and selected metabolites. The abbreviations provided in Table 1-1 are used throughout this report. Phthalates are used to impart flexibility to plastics and for their solvent properties. They are used in a wide variety of consumer products, including cosmetics, personal-care products, pharmaceuticals, medical devices, childrenâs toys, food packaging, and cleaning and building materials (Schettler 2006). The widespread use of phthalates has raised concerns regarding potential human exposure. As part of the 1999-2000 National Health and Nutrition Examination Survey (NHANES), the Centers for Disease Control and Prevention (CDC) measured several phthalate monoesters (metabolites of the diesters) in urine (Silva et al. 2004). Later surveys have provided additional data on phthalate exposure (CDC 2007a,b). Those and other surveys indicate widespread human exposure to various phthalates (Hauser and Calafat 2005). Phthalate exposures can produce a variety of effects in laboratory animals; however, their adverse effects on the development of the reproductive system of male animals have led to particular concern. The effects of fetal exposure of male laboratory animals include infertility, decreased sperm count, crypt- orchidism (undescended testes), hypospadias (malformation of the penis in which the urethra does not open at the tip of the organ), and other reproductive tract malformations and are similar to those that characterize the hypothesized testicular dysgenesis syndrome in humans (SkakkebÃ¦k et al. 2001). Currently, epidemiologic evidence of adverse human health effects of phthalate exposure is inadequate or limited (Hauser and Calafat 2005). Recently, the European Union FIGURE 1-1 General chemical structure of an o-phthalate.
TABLE 1-1 Phthalate Parent Compounds and Selected Metabolites CAS Registry Molecular Phthalate Number Weight Selected Metabolites DMP dimethyl phthalate 131-11-3 194 MMP monomethyl phthalate DEP diethyl phthalate 84-66-2 222 MEP monoethyl phthalate DBP di-n-butyl phthalate 84-74-2 278 MBP monobutyl phthalate DIBP diisobutyl phthalate 84-69-5 278 MIBP monoisobutyl phthalate BBP butyl benzyl phthalate 85-68-7 312 MBZP monobenzyl phthalate DCHP dicyclohexyl phthalate 84-61-7 330 MCHP monocyclohexyl phthalate DEHP di(2-ethylhexyl) phthalate 117-81-7 390 MECPP mono(2-ethyl-5-carboxypentyl) phthalate MEOHP mono(2-ethyl-5-oxohexyl) phthalate MEHHP mono(2-ethyl-5-hydroxyhexyl) phthalate MEHP mono(2-ethylhexyl) phthalate DOP di-n-octyl phthalate 117-84-0 390 MCPP mono-3-carboxypropyl phthalate MOP mono-n-octyl phthalate (Continued) 15
16 TABLE 1-1 Continued CAS Registry Molecular Phthalate Number Weight Selected Metabolites DINP diisononyl phthalate 28553-12-0 419 MCIOP mono(carboxyisooctyl) phthalate MHINP mono(hydroxyisononyl) phthalate MOINP mono(oxoisononyl) phthalate MINP monoisononyl phthalate DIDP diisodecyl phthalate 26761-40-0 447 MCINP mono(carboxyisononyl) phthalate MHIDP mono(hydroxyisodecyl) phthalate MOIDP mono(oxoisodecyl) phthalate MIDP monoisodecyl phthalate DPHP di(2-propylheptyl) phthalate 53306-54-0 447 MCPHP mono(carboxypropylheptyl) phthalate MHPHP mono(hydroxypropylheptyl) phthalate MOPHP mono(oxopropylheptyl) phthalate MPHP monopropylheptyl phthalate
Introduction 17 (EU 2005a) and the United States1 have passed legislation that restricts the con- centration of selected phthalates in childrenâs toys, and the European Union has banned several phthalates from cosmetics (EU 2004, 2005b). THE COMMITTEEâS TASK AND APPROACH The widespread human exposure to phthalates coupled with the ability of this chemical class to induce male reproductive toxicity in laboratory animals prompted EPAâs request to the NRC to conduct an independent scientific evaluation of phthalates in the context of cumulative risk assessment. Specifi- cally, the committee was asked to review critical scientific data and address questions related to the human relevance of experimental data, modes of action, exposure information, dose-response relationships, and the potential for cumula- tive effects. The committee was further asked to consider the strengths and weaknesses of cumulative-assessment approaches, to provide recommendations to EPA on conducting a cumulative risk assessment of phthalate chemicals, and to identify additional research needs. Finally, the committee was asked to con- sider the applicability of its recommendations to cumulative risk assessment of other chemical classes. See Appendix A for a verbatim statement of task. Given the statement of task, the committee members were selected for their expertise in biostatistics, epidemiology, exposure assessment, toxicology, pediatrics, risk assessment, cumulative risk assessment, and risk management. See Appendix B for biographic information on the committee. To accomplish its task, the committee held five meetings from December 2007 to June 2008. In public sessions during the first two meetings, the commit- tee heard presentations from the sponsor and invited speakers from government agencies, academe, industry, and environmental groups. The committee re- viewed numerous scientific publications on cumulative risk assessment, phthal- ate exposure, and phthalate toxicity. The committee first focused on the central question of whether a cumulative risk assessment is appropriate for the phthalate esters. Given the committeeâs agreement that a cumulative risk assessment was warranted, it focused on approaches to such an assessment. Particular weight was given to approaches that would help the process to evolve and would be applicable to the real-world context in which humans are exposed to a variety of structurally and nonstructurally related chemicals. Accordingly, this report is not a comprehensive toxicologic profile, nor is it a cumulative risk assessment, of phthalates. Furthermore, although the committee clearly recognized that cumula- tive risk assessment must encompass the assessment of multiple agents and other stressors to which people are exposed by multiple pathways and routes and for varied durations and that cause varied health effects, it restricted its examina- tion to the most sensitive outcomes (that is, effects on the development of the male reproductive system) exhibited in laboratory animals as a result of phthal- 1 Consumer Product Safety Improvement Act of 2008, Title II Â§108 (a)(b) (H.R. 4040).
18 Phthalates and Cumulative Risk Assessment: The Tasks Ahead ate exposure. As a final consideration, the committee evaluated the applicability of the proposed approaches to other chemical classes and more broadly to chemicals that produce common adverse outcomes. ORGANIZATION OF THE REPORT The committeeâs report is organized into six chapters and four appendixes. Chapter 2 summarizes sources and routes of phthalate exposure, reviews avail- able exposure data, and discusses phthalate metabolism. Chapter 3 reviews tox- icity, particularly developmental toxicity in the male reproductive system, that results from phthalate exposure. Chapter 4 provides a synopsis of current risk- assessment practices and identifies their strengths and weaknesses. Chapter 5 addresses whether a cumulative risk assessment is appropriate for phthalates, recommends approaches for such an assessment, and discusses the applicability of the approaches to other chemicals. Chapter 6 identifies needed data and re- search that could help to refine a cumulative risk assessment of phthalates and reduce the associated uncertainty. Appendix A is the verbatim statement of task, Appendix B provides biographic information on the committee, Appendix C provides the committeeâs reanalysis of some phthalate-mixture data, and Ap- pendix D is a case study that illustrates one risk-assessment approach suggested by the committee. REFERENCES CDC (Centers for Disease Control and Prevention). 2007a. National Health and Nutrition Examination Survey Data: 2001-2002. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics, Hyattsville, MD [online]. Available: http://www.cdc.gov/nchs/about/ major/nhanes/nhanes01-02.htm [accessed June 10, 2008]. CDC (Centers for Disease Control and Prevention). 2007b. National Health and Nutrition Examination Survey Data: 2003-2004. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics, Hyattsville, MD [online]. Available: http://www.cdc.gov/nchs/about/ major/nhanes/nhanes2003-2004/nhanes03_04.htm [accessed June 10, 2008]. EPA (U.S. Environmental Protection Agency). 1986. Guidelines for the Health Risk As- sessment of Chemical Mixtures. EPA/630/R-98/002. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. September 1986 [online]. Available: http://www.epa.gov/NCEA/raf/pdfs/chem_mix/chemmix_ 1986. pdf [accessed Aug. 11, 2008]. EPA (U.S. Environmental Protection Agency). 1987. Interim Procedures for Estimating Risks Associated with Exposures to Mixtures of Chlorinated Dibenzo-p-Dioxins and -Dibenzofurans (CDDs and CDFs). EPA/625/3-87/012. Risk Assessment Fo- rum, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=20007V43.txt [accessed Nov. 12, 2008].
Introduction 19 EPA (U.S. Environmental Protection Agency). 1989. Interim Procedures for Estimating Risks Associated with Exposures to Mixtures of Chlorinated Dibenzo-p-Dioxins and -Dibenzofurans (CDDs and CDFs) and 1989 Update. EPA/625/3-89/016. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. March 1989 [online]. Available: http://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey= 300047JJ.txt [accessed Nov. 12, 2008]. EPA (U.S. Environmental Protection Agency). 1993. Provisional Guidance for Quantita- tive Risk Assessment of Polycyclic Aromatic Hydrocarbons. EPA/600/R-93/089. Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. July 1993 [online]. Available: http://www.epa.gov/oswer/ riskassessment/pdf/1993_epa_600_r-93_c89.pdf [accessed June 10, 2008]. EPA (U.S. Environmental Protection Agency). 1997. Guidance on Cumulative Risk As- sessment. Part I Planning and Scoping, EPA Science Policy Council, July 3, 1997, and Memo from the EPA Administrator, July 3, 1997 [online]. Available: http://www.epa.gov/OSA/spc/pdfs/cumrisk2.pdf and http://www.epa.gov/OSA/ spc/pdfs/cumulrisk.pdf [accessed July 13, 2008]. EPA (U.S. Environmental Protection Agency). 2000. Supplementary Guidance for Con- ducting Health Risk Assessment of Chemical Mixtures. EPA/630/R-00/002. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. Au- gust 2000 [online]. Available: http://www.epa.gov/NCEA/raf/pdfs/chem_mix/ chem_mix_08_2001.pdf [accessed June 10, 2008]. EPA (U.S. Environmental Protection Agency). 2002. Guidance on Cumulative Risk As- sessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity. Office of Pesticide Programs, U.S. Environmental Protection Agency, Washing- ton, DC. January 14, 2002 [online]. Available: http://www.epa.gov/oppfead1/trac/ science/cumulative_guidance.pdf [accessed June 10, 2008]. EPA (U.S. Environmental Protection Agency). 2003. Framework for Cumulative Risk Assessment. EPA/630/P-02/001F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. May 2003 [online]. Available: oaspub.epa. gov/eims/eimscomm.getfile?p_download_id=36941 [accessed June 10, 2008]. EPA (U.S. Environmental Protection Agency). 2006. Considerations for Developing Alternative Health Risk Assessment Approaches for Addressing Multiple Chemi- cals, Exposures and Effects (External Review Draft). EPA/600/R-06/013A. Na- tional Center for Environmental Assessment, Office of Research and Develop- ment, U.S. Environmental Protection Agency, Cincinnati, OH. March 2006 [online]. Available: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=149983 [accessed June 2008]. EPA (U.S. Environmental Protection Agency). 2007. Concepts, Methods, and Data Sources for Cumulative Health Risk Assessment of Multiple Chemicals, Expo- sures and Effects: A Resource Document. EPA/600/R-06/013F. National Center for Environmental Assessment, Office of Research and Development, U.S. Envi- ronmental Protection Agency, Cincinnati, OH, in collaboration with U.S. Depart- ment of Energy, Argonne National Laboratory, Environmental Assessment Divi- sion, Argonne, IL. August 2007 [online]. Available: http://cfpub.epa.gov/ncea/ cfm/recordisplay.cfm?deid=190187 [accessed Nov. 12, 2008]. EU (European Union). 2004. Commission Directive 2004/93/EC of 21 September 2004 Amending Council Directive 76/768/EEC for the Purpose of Adapting its Annexes II and III to Technical Progress. Official Journal of European Union I.300:13-41. Sept. 25, 2004 [online]. Available: http://ec.europa.eu/enterprise/cosmetics/doc/ 2004_93/en.pdf [accessed Oct. 21, 2008].
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