4
Current Practice in Risk Assessment and Cumulative Risk Assessment

Chapter 2 summarizes the evidence on human exposure to phthalates and demonstrates that there is ample evidence of simultaneous exposure of most of or all the U.S. population to multiple phthalates. Chapter 3 examines the toxicity, as seen primarily in laboratory animal models, of individual phthalates and of other agents that produce effects similar to those seen on exposure to individual phthalates. The exposure and toxicity information clearly indicates that some sort of cumulative risk assessment is required in examining phthalate exposure. To place the discussions of Chapter 5 in context, it is useful to observe what is currently done when risks posed by multiple chemical exposures are evaluated with standard techniques according to guidance of the U.S. Environmental Protection Agency (EPA) and to examine how the guidance has evolved.

CURRENT RISK-ASSESSMENT APPROACHES AND PRACTICES

The most extensive and detailed guidance on typical risk assessments is in the Risk Assessment Guidance for Superfund (RAGS), particularly Volume I, Human Health Evaluation Manual (Part A) (EPA 1989a) and later published guidance supporting RAGS. This chapter features a description of how risk assessment is performed with RAGS because it (as intended according to its statement of purpose) tends to inform risk-assessment practice in other EPA programs and under other regulatory authorities. Additional guidance documents are cited where needed. EPA guidance on cumulative exposure and risk has evolved over the last couple of decades, and the relevant developments are discussed near the conclusion of this chapter in the section “The Evolution of Guidance on Cumulative Risk Assessment.” The chapter concludes with a summary of recent cumulative exposure and risk evaluations.

The reason for considering RAGS and the actual procedures that are used in the field is to emphasize that what is done in site-specific risk assessments (for example, at Superfund sites) is distinct from the approaches and procedures



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4 Current Practice in Risk Assessment and Cumulative Risk Assessment Chapter 2 summarizes the evidence on human exposure to phthalates and demonstrates that there is ample evidence of simultaneous exposure of most of or all the U.S. population to multiple phthalates. Chapter 3 examines the toxic- ity, as seen primarily in laboratory animal models, of individual phthalates and of other agents that produce effects similar to those seen on exposure to individ- ual phthalates. The exposure and toxicity information clearly indicates that some sort of cumulative risk assessment is required in examining phthalate exposure. To place the discussions of Chapter 5 in context, it is useful to observe what is currently done when risks posed by multiple chemical exposures are evaluated with standard techniques according to guidance of the U.S. Environmental Pro- tection Agency (EPA) and to examine how the guidance has evolved. CURRENT RISK-ASSESSMENT APPROACHES AND PRACTICES The most extensive and detailed guidance on typical risk assessments is in the Risk Assessment Guidance for Superfund (RAGS), particularly Volume I, Human Health Evaluation Manual (Part A) (EPA 1989a) and later published guidance supporting RAGS. This chapter features a description of how risk as- sessment is performed with RAGS because it (as intended according to its statement of purpose) tends to inform risk-assessment practice in other EPA programs and under other regulatory authorities. Additional guidance documents are cited where needed. EPA guidance on cumulative exposure and risk has evolved over the last couple of decades, and the relevant developments are dis- cussed near the conclusion of this chapter in the section “The Evolution of Guidance on Cumulative Risk Assessment.” The chapter concludes with a summary of recent cumulative exposure and risk evaluations. The reason for considering RAGS and the actual procedures that are used in the field is to emphasize that what is done in site-specific risk assessments (for example, at Superfund sites) is distinct from the approaches and procedures 68

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69 Current Practice in Risk Assessment and Cumulative Risk Assessment used in setting standards or guidelines for individual chemicals. Although both draw heavily on toxicity assessments—for example, as appear on or are used by EPA’s Integrated Risk Information System (IRIS) web site—the application of the toxicity assessments typically differs considerably between the two. Site- specific risk assessments are often concerned with simultaneous evaluation of multiple chemicals, multiple pathways of exposure, multiple routes of exposure, and multiple receptors. Standard-setting or guideline-setting generally evaluates at one time single chemicals, single routes of exposure, and single receptors, although there are exceptions, such as disinfection byproducts in drinking water. The committee’s task of evaluating the potential for a cumulative risk as- sessment of phthalates has to take into account that such cumulative assessments are commonly performed already, and any recommendations of the committee should be compared with the current EPA approach as described in RAGS and related guidance. Accordingly, the following sections discuss what is typically required in the exposure-assessment, toxicity-assessment, and risk- characterization parts of a risk assessment. The approaches are evaluated for what they imply about cumulative assessment of phthalates in various EPA pro- grams, such as those involving Superfund, air toxics, and drinking water. Exposure Assessment The exposure-assessment component of a risk assessment of hazardous chemicals according to RAGS (EPA 1989a) requires evaluation of exposure of all the relevant, although not personally identified, people (“receptors”) to all the relevant chemicals through all the relevant pathways by all the relevant routes of exposure for all relevant periods. The products of exposure assessment are esti- mates of exposure of defined receptors to each chemical disaggregated by peri- ods and exposure pathways. This section provides an idealized general descrip- tion, not a critical review, of the current practice of exposure assessment. Persons Whose Exposure Is Quantified The relevant receptors to evaluate are typically intended to be persons who experience the “reasonable maximum exposure” (RME) and persons who ex- perience “central-tendency” (CT) exposures. The RME is the highest exposure that is expected to occur (EPA 1989a, 1992), and EPA (2001) advises that risk managers using probabilistic risk assessment should select the RME from the upper end of the range of risk estimates, “generally between the 90th and 99.9th percentiles” (EPA 2001). Later discussion focuses on persons who experience the RME because their exposure usually forms the basis of EPA decision- making (CT estimates may be needed for some pathways of the RME, as de- scribed below).

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70 Phthalates and Cumulative Risk Assessment: The Tasks Ahead Chemicals Warranting Quantitative Dose Estimation The relevant chemicals to evaluate in an exposure assessment are those which pass an initial screening evaluation that is used to eliminate chemicals that are clearly of no concern. The evaluation will typically first examine any available observations for frequency of occurrence and concentrations of chemi- cals in whatever physical media have been examined; this eliminates chemicals that occur very rarely and at concentrations much lower than risk-based screen- ing values—precalculated values that, if they were carried through a risk as- sessment, would result in risk estimates small enough to be ignored. Where the only concern is increments of exposure above background, chemicals whose concentrations are similar to background may also be eliminated from further consideration. Further screening may be performed to demonstrate that even worst-case exposures (based on upper-bound estimates of exposure) present no hazard. An exposure assessment is typically applied for many chemicals, although usually the nature of the expected major contamination is known to some de- gree. For example, the initial list of chemicals to be evaluated in a typical site risk assessment is usually the Contract Laboratory Program Target Compound and Target Analyte List (TCP/TAL, see EPA 2008a), combined with any site- specific chemicals known to be present and to have potential toxicity. The TCP/TAL (as of May 2008) includes 52 volatile chemicals, 30 pesticides and Aroclors, 23 metals, cyanide, and 67 semivolatile chemicals. The semivolatile chemicals include six phthalates: DMP, DEP, DBP, BBP, DEHP, and DOP. For an exposure assessment performed for a risk assessment at a contami- nated site—for example, a Superfund site or a site evaluated under similar state programs—environmental samples will often be tested for all chemicals on the TCP/TAL or similar lists, augmented where necessary. An initial screening for the full list of chemicals may be performed on a small number of samples cho- sen from areas thought to be most contaminated (for example, because of visual observation of soil staining, according to known locations of potentially con- taminating processes, or on the basis of on-site screening with vapor detectors or conductivity measurements), and chemicals that are not detected may be dropped from the analytic sample suite. Later samples may be analyzed for a smaller list of chemicals. As discussed above, not all the chemicals analyzed will be evaluated through all parts of the exposure and risk assessment; applica- tion of screening approaches may allow chemicals to be dropped from some exposure pathways or for some receptors. For some sites or situations, there will be evaluation of special compounds not included in the lists described or special analyses of the compounds listed. For example, where contamination by poly- chlorinated dibenzo-p-dioxins (PCDDs) or polychlorinated dibenzo-p-furans (PCDFs) is suspected or found in an initial screening, analyses of various PCDD or PCDF congeners may be conducted.

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71 Current Practice in Risk Assessment and Cumulative Risk Assessment Exposure Pathways and Periods Evaluated Exposure assessment should take account of all the exposure pathways that can occur for any person. The relevant pathways included are all those by which some chemical may travel and cause exposure to the chosen receptors (that is, complete pathways). The relevant routes of exposure (ingestion, inhala- tion, and dermal contact) are all that may occur at the end of any particular pathway; in special circumstances, other routes, such as injection or transmuco- sal absorption, might have to be considered. The relevant periods depend on the toxic characteristics of the chemicals evaluated and on the timing and pattern of exposure but typically are handled by estimating exposure averaged over fixed periods for various locations and characteristics of receptors—such as age, sus- ceptibility, and habits. Typically, assessments will evaluate acute exposure (from instantaneous to a few days long), subchronic exposure (from a few days to about 7 years), and chronic exposure (extending to a lifetime). Total Doses Estimated for Each Receptor For each pathway, the exposures of the receptor who experiences the RME are obtained by using procedures that result in estimates at the upper end of likely exposures, but the extent of any underestimation or overestimation is not generally known. More complex procedures, such as probabilistic methods, may be used to obtain better estimates of explicit percentiles of the exposure distribu- tion. If it is determined that combined exposure (from multiple pathways) can occur, receptors who experience the RME are defined for combinations, and upper-end estimates of combined exposures are obtained by summing suitable combinations of estimates for each pathway. Such combinations may involve upper-end estimates for one or more pathways and average estimates for others. The aim is to obtain exposure estimates that are at the upper end of the actual or potential exposure. The result is a total dose estimate for each receptor, disag- gregated by chemical, route of exposure, and period. Toxicity Assessment As in the preceding section, this section provides an idealized general de- scription, not a critical review, of the current practice of toxicity assessment. General Approach The practical and most commonly adopted approach to toxicity assess- ment in EPA risk assessments is to obtain toxicity values from the EPA IRIS database for chronic oral reference doses (RfDs), chronic inhalation reference concentrations (RfCs), cancer classification, ingestion and inhalation cancer

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72 Phthalates and Cumulative Risk Assessment: The Tasks Ahead slope factors (CSFs for lifetime exposure), and inhalation and ingestion unit risks (URs for lifetime exposure). (See Box 4-1 for how those quantities are defined by EPA on its IRIS web site.1) In some cases, such as that of vinyl chlo- ride, IRIS provides modifications of the values, for example, separate estimates of oral CSF or UR for continuous lifetime exposure during adulthood and for continuous lifetime exposure from birth. BOX 4-1 EPA Definitions for Toxicity Values Cancer Evaluations Cancer slope factor (CSF): An upper bound, approximating a 95% confidence limit, on the increased cancer risk from a lifetime exposure to an agent. This estimate, usually expressed in units of proportion (of a population) affected per mg/kg-day, is generally reserved for use in the low- dose region of the dose-response relationship, that is, for exposures corresponding to risks less than 1 in 100. Unit risk (UR): The upper-bound excess lifetime cancer risk estimated to result from continuous exposure to an agent at a concentration of 1 µg/L in water, or 1 µg/m3 in air. The interpretation of unit risk would be as follows: if unit risk = 2 x 10-6 per µg/L, 2 excess cancer cases (upper bound estimate) are expected to develop per 1,000,000 people if exposed daily for a lifetime to 1 µg of the chemical in 1 liter of drinking water. Noncancer Evaluations Reference concentration (RfC): An estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. It can be derived from a NOAEL [no-observed-adverse-effect level], LOAEL [lowest observed-adverse-effect level], or benchmark concentration, with uncertainty factors generally applied to reflect limitations of the data used. Reference dose (RfD): An estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. It can be derived from a NOAEL, LOAEL, or benchmark dose, with uncertainty factors generally applied to reflect limitations of the data used. Source: EPA 2008b. 1 The committee has not examined whether the values used by EPA meet the defini- tions.

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73 Current Practice in Risk Assessment and Cumulative Risk Assessment IRIS is at the top of EPA’s recommended three-tier hierarchy of sources for toxicity values for use at Superfund sites (EPA 1993a, 2003a); more broadly, IRIS values support EPA policy-making activities (EPA 2008c). When IRIS does not provide toxicity values or when toxicity values are needed for circum- stances not typically provided for in IRIS (for example, for evaluation of sub- chronic or acute exposures2), the recommended hierarchy of sources is searched sequentially for suitable values. However, EPA recognizes that the hierarchy does not address situations where new toxicity information is brought to its at- tention. Therefore, although in practice risk assessments typically incorporate previously developed toxicity values, especially IRIS values, new information could result in the development and application of toxicity values other than those in EPA’s hierarchy. The derivation of toxicity values for non-EPA risk assessments, such as those performed for or by state agencies, typically follows the same patterns as for EPA’s risk assessments for Superfund sites. Toxicity values are typically predefined by a state agency with jurisdiction, usually by reference to a hierar- chy of sources of toxicity values prepared by other suitably authoritative sources, although the hierarchy may differ from EPA’s and from state to state. The Environmental Protection Agency’s IRIS Process The output of the IRIS process is a set of toxicity values that can be used in site-specific risk assessment, such as for Superfund sites; product-specific risk assessments, such as those for consumer products; media-specific risk assessments, such as for drinking-water standards; and other applications of risk assessment. Those conducting the risk assessments must confirm the relevance of IRIS values for the chemical species, exposure pathway, exposure timeframe (nearly all toxicity values on IRIS apply to the evaluation of chronic exposures), and population under evaluation (for example, in case the population might have increased susceptibility with respect to life stage, disease status, or genetic predisposition that is not already accounted for in development of the toxicity value). The IRIS database on a chemical contains the toxicity values and brief summaries of toxicity data and other information that support them. Since 1997, the database summaries have been supplemented by detailed toxicologic reviews that undergo an independent expert peer review, including the opportunity for public review and comment. Toxicologic reviews summarize a chemical’s properties, toxicokinetics, pharmacokinetic modeling where available, hazard identification based on epidemiologic studies, animal studies, in vivo and in vitro assays, and mechanism-of-action and dose-response data and culminate in quantitative recommendations for toxicity values when sufficient data are 2 A recent exceptional case that provides values for subchronic and acute exposures is that of 1,1,1-trichloroethane (see EPA 2007a).

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74 Phthalates and Cumulative Risk Assessment: The Tasks Ahead available to support them. In conducting toxicologic reviews, EPA uses relevant guidance that includes evaluation of the array of possible health outcomes, such as cancer, neurotoxicity, developmental toxicity, and reproductive toxicity. Toxicity Values Currently Available for Phthalates Table 4-1 summarizes toxicity values currently available for phthalates in the EPA hierarchy of sources.3 IRIS provides a limited set of toxicity values for five phthalates. As discussed earlier, IRIS values make up the highest tier in EPA’s hierarchy of toxicity values (EPA 2003a), and EPA generally favors their use, when available, over lower-tier toxicity values. Provisional peer-reviewed toxicity values (PPRTVs) make up the second tier of toxicity values and are developed by the Superfund Health Risk Technical Support Center (STSC). The STSC has assigned a PPRTV to BBP and a “screening value” to DMP, which are available with supporting documentation internally to EPA and on request to registered users. The third tier of EPA’s hierarchy of toxicity values, which is a catch-all for “other toxicity values,” includes California Environmental Protection Agency Maximum Allowable Dose Levels (MADLs) and Agency for Toxic Substances and Disease Registry (ATSDR) minimal risk levels (MRLs). California has established MADLs for two phthalates, DEHP and DBP; however, the value for DBP is not in the database identified in the EPA procedure (EPA 2003a) for locating other toxicity values, so it has not been included in Table 4-1. ATSDR has established MRLs based on noncancer end points for four phthalates: DEHP (reproduction end point), DBP (developmental end point), DOP (hepatic end point), and DEP (reproductive and hepatic end points). Only the MRL for DEHP applies to the evaluation of chronic exposures, defined by ATSDR as lasting over 365 days. The other MRLs apply to acute exposure (1-7 days) and intermediate exposure (7-364 days). Only three of the seven phthalates known to cause phthalate syndrome in rats (see Table 3-3) have toxicity values in this hierarchy. Furthermore, the val- ues are based on nonreproductive toxicities with the exception of the ATSDR MRL and the California MADLs for DEHP, and two others (DMP and DEP) are listed that have not been associated with phthalate syndrome. The screening value for DMP developed by EPA’s STSC is based on a lowest observed- adverse-effect level associated with increased absolute and relative liver weight and decreased serum and testicular testosterone in weanling male rats. Despite noting the observed lack of adverse effects of DMP on reproductive outcomes or fetal development, the authors of the screening value concluded that “exposure 3 The committee notes that it was not charged with reviewing the basis or adequacy of the values reported in Table 4-1; the committee is simply reporting the current toxicity values for phthalates.

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TABLE 4-1 Summary of EPA’s Toxicity Values for Phthalatesa Phthalateb Chronic Oral Reference Chronic Inhalation Reference Oral Slope Factor (mg/kg-d)-1 Inhalation Unit Risk (µg/m3)-1 CAS No. Dose (mg/kg-d) Concentration (mg/m3) DMP CAS Not available (3/1/1994)c Not available (10/1/1990); EPA Not available; “D”–not Not available; “D”–not classifiable 131-11-3 contractor updated review classifiable (2/1/1993), EPA (2/1/1993), EPA contractor updated (8/2003) contractor updated review review (8/2003) (8/2003) Not available Not available; “D”–not Not available; “D”–not classifiable DEP CAS 0.8 mg/kg-d; NOAEL, 750 classifiable (2/1/1993); EPA (2/1/1993); EPA contractor updated 84-66-2 mg/kg-d; uncertainty factor, contractor updated review review (9/2002) 1,000 (9/2002) Critical effects from rat subchronic feeding study: decreased growth rate, decreased food consumption, and altered organ weights Low confidence (2/1/1993) EPA contractor updated review (9/2002) DBP CAS 0.1 mg/kg-d; NOAEL, 125 Not available (10/1/1990); EPA Not available; “D”–not Not available; “D”–not classifiable (2/1/1993); EPA contractor updated 84-74-2 mg/kg-d; uncertainty factor, contractor updated review classifiable (2/1/1993); EPA review (11/2001) 1,000 (11/2001) contractor updated review (11/2001) Critical effect from rat subchronic-to-chronic oral study: increased mortality Low confidence (8/1/1990) EPA contractor updated review (11/2001) (Continued) 75

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76 TABLE 4-1 Continued Phthalateb Chronic Oral Reference Chronic Inhalation Reference Oral Slope Factor (mg/kg-d)-1 Inhalation Unit Risk (µg/m3)-1 CAS No. Dose (mg/kg-d) Concentration (mg/m3) Proposed (6/2006): 0.3 mg/kg-d (acute, short term, subchronic, chronic); NOAEL, 30 mg/kg-d; uncertainty factor, 100; critical effect from rat developmental oral gavage study: developmental (decrease in fetal testosterone) Not available BBP CAS 0.2 mg/kg-d; NOAEL, 159 Not available; “C”–possible Not available; “C”–possible human 85-68-7 mg/kg-d; uncertainty factor, human carcinogen (2/1/1993); carcinogen (2/1/1993); EPA 1000 “qualitative weaknesses of the contractor updated review (8/2003) mononuclear cell leukemia Critical effects from 6-mo rat response do not provide a feeding study: significantly compelling basis to model the increased liver-to-body weight dose-response data,” EPA and liver-to-brain weight ratios contractor updated review Low confidence (2/1/1993) (8/2003) EPA contractor updated review PPRTV: 1.9 × 10-3 (10/1/2002); (8/2003) pancreatic cancer in male rats Not available DEHP CAS 0.02 mg/kg-d; LOAEL 19 1.4 × 10-2; “B2”–probable Not available 117-81-7 mg/kg-d; uncertainty factor, human carcinogen (2/1/1993); 1000 “orally administered DEHP produced significant dose-related Critical effect from guinea pig increases in liver tumor subchronic-to-chronic oral responses in rats and mice of bioassay: increased relative liver both sexes” weight Medium confidence (5/1/1991)

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California EPA:f Oral CSF, California EPA:f inhalation unit ATSDR MRL:d 0.06; uncertainty 3 × 10-3 risk, 2.4 × 10-6 factor, 100; health end point, reproduction (9/2002) California EPA:e 410 µg/d (adults); 58 µg/d (infant boys, age 29 days-24 months); 20 µg/d (neonatal infant boys, age 0-28 days) a Date of last review is shown in parentheses. Except where otherwise noted, toxicity values are from EPA’s IRIS database because these values repre- sent the highest tier in EPA’s hierarchy of toxicity values for use at Superfund sites (EPA 2003a). b EPA’s IRIS database includes a summary profile of one other phthalate: dimethyl terephthalate (DMT) (CAS 120-61-6); synonym: dimethyl-p- phthalate. However, this phthalate is not a diester of 1,2-benzenedicarboxylic acid, so it was not considered by the committee. c EPA’s Superfund Health Risk Technical Support Center developed a screening value for DMP (dated September 25, 2007) that probably falls in the third tier of the three-tier hierarchy of toxicity values. It is a subchronic RfD of 0.1 mg/kg-d that incorporates an uncertainty factor of 3,000 and is based on a LOAEL associated with increased absolute and relative liver weight and decreased serum and testicular testosterone in male rats. The authors of the PPRTV documentation concluded that “exposure to multiple phthalate esters in the environment should be taken into consideration when conduct- ing a risk assessment for DMP” (EPA 2007b, p. 15). d Agency for Toxic Substances Disease Registry minimal risk level (ATSDR 2007a). MRLs are also available for three other phthalates to evaluate ex- posures lasting less than 1 year. e These values are Maximum Allowable Dose Levels (MADLs) for chemicals causing reproductive toxicity. Levels for male children and adolescents can be calculated by application of the default body weights in Title 22, California Code of Regulations, Section 12703(a)(8) to the procedure specified in Title 22, California Code of Regulations, Sections 12801 and 12803. California EPA also established the following MADLs for intravenous expo- sure: 4,200 µg/d (adults), 600 µg/d (infant boys, age 29 days-24 months), 210 µg/d (neonatal infant boys, age 0-28 days). f California EPA, Office of Environmental Health Hazard Assessment. See OEHHA (2008). 77

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78 Phthalates and Cumulative Risk Assessment: The Tasks Ahead to multiple phthalate esters in the environment should be taken into considera- tion when conducting a risk assessment for DMP,” justifying the statement with the observation that “several phthalate esters may have a common endpoint of toxicity related to developmental and reproductive effects” (EPA 2007b, p. 15). The hierarchy’s entries clearly are largely out of date; any specialized risk assessment of phthalates would presumably consult the recent literature and take account of reproductive toxicity. However, at, for example, a Superfund site, multiple phthalates might be evaluated with the values in Table 4-1. Special Cases For some chemicals or chemical classes—such as anticholinesterase- acting pesticides, PCDDs and PCDFs, polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons—EPA has adopted special approaches that incorporate cumulative risk assessment. Those chemicals are discussed in the section “Current Environmental Protection Agency Cumulative Risk Assess- ment Examples and Case Studies” below. When chemicals or exposure circumstances are not suitably matched by any toxicity values in the defined hierarchy of sources discussed above, those performing risk assessments for EPA, such as for Superfund sites, may call on EPA’s National Center for Environmental Assessment for assistance (this would presumably occur for phthalates not included in Table 4-1). For others doing risk assessments, evaluation of toxicity values for use in risk assessments is a matter of individual choice. Some toxicity values may be derived by a risk as- sessor, for example, for assessments appearing in the peer-reviewed literature. In general, the context of the risk assessment dictates the method used to determine the toxicity values. Risk Characterization of Mixtures: Dose Addition and Independent Action As pointed out above, many risk assessments performed by using current EPA guidance evaluate simultaneous exposure to multiple chemicals (mixtures), multiple pathways of exposure, multiple routes of exposure, and multiple time- frames of exposure. Before discussing the standard approach to characterizing the risks posed by such exposures, it is helpful to discuss some general concepts of mixture evaluation. Many terms have been introduced into the literature to describe the com- bined effect on a particular end point of two or more agents acting simultane- ously in comparison with the effect of each agent acting alone. However, the terms have often been used confusingly, contradictorily, inconsistently, or incor- rectly (Berenbaum 1989). Some of the confusion and inconsistency in nomen- clature stems from attempts to evaluate the combined effects of multiple agents in terms of postulated mechanisms of action rather than in terms of the observed dose-response curves for a given effect. It is unnecessary (although not forbid-

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95 Current Practice in Risk Assessment and Cumulative Risk Assessment CURRENT ENVIROMENTAL PROTECTION AGENCY EXAMPLES AND CASE STUDIES OF CUMULATIVE RISK ASSESSMENT Cumulative risk assessment is not new, although development and appli- cation of relevant EPA guidance continues to evolve (see, for example, EPA 2007g). EPA’s IRIS database includes toxicity values for chemical mixtures, such as coke-oven emissions, diesel-engine exhaust, PCBs, xylene isomers, a 2,4- and 2,6-dinitrotoluene mixture, and a 2,4- and 2,6-toluene diisocyanate mixture. In addition, Table 4-3 highlights recent applications of cumulative risk assessment to evaluate human exposure to chemicals. The following sections provide more detailed descriptions of two EPA programs that involve cumula- tive evaluations of pesticides and air toxics. Aggregate and Cumulative Assessments of Pesticides EPA’s Office of Pesticide Programs implements a two-stage assessment process for groups of pesticides that have a common mechanism of toxicity. First, an aggregate assessment that considers all pathways and routes of expo- sure of each member of the group is completed (EPA 2008d,e); depending on the results, risk-reduction actions may be taken. Then a cumulative assessment considers exposure of and risks to all members of the group; additional risk- reduction steps may be taken on the basis of the results. Risk-reduction actions include elimination or restriction of pesticide uses. Cumulative risk assessments of pesticides with a common mechanism of toxicity involve extensive dose-response modeling for each pesticide, which provides the relative potencies used in the dose-additivity-based cumulative method for common-mechanism pesticides (EPA 2002). Such risk assessments also involve a multicomponent exposure assessment (EPA 2002). Dietary expo- sures are estimated from nationally representative dietary and pesticide-residue surveys. Drinking-water exposures and residential and nonoccupational pesti- cide uses are estimated by region to reflect variations in agriculture, pest pres- sures, and home and other pesticide uses. The datasets are compiled into an in- dividual-level daily-exposure estimate over the course of a year. For the risk characterization, relevant durations of exposure are defined, and rolling-average exposures to individuals are developed on the basis of the daily-exposure esti- mates (EPA 2002). As implied in the descriptions of dose-response and expo- sure-assessment procedures, cumulative risk assessments of common- mechanism pesticides involve consideration of the timing and duration of expo- sures and the timing of onset and duration of health effects and recovery (EPA 2002).

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96 TABLE 4-3 Summary of Cumulative Human Risk Assessment Applications to Evaluation of Chemical Exposuresa Chemical Cumulative Risk Assessment Approach References Mixture Asbestos fibers Asbestos includes various naturally occurring silicate fibers, and their cancer potency may vary as a function of fiber EPA 2008f type and size. Therefore, EPA developed draft guidance, currently undergoing review by its Science Advisory Board, that provides an approach for quantifying differences in cancer potency among fiber types (amphibole or chrysotile) and particle sizes (length and width). EPA 1993b; Carcinogenic EPA classifies benzo[a]pyrene (B[a]P) and six other polycyclic aromatic hydrocarbons (PAHs) as B2 carcinogens. Carlson-Lynch polycyclic Results are consistent among cancer bioassays involving B[a]P and these PAHs; however, insufficient data are et al. 2007 aromatic available to derive cancer slope factors for all these PAHs. Also, although these PAHs may cause cancer by the same hydrocarbons mechanism as B[a]P, they appear to be less potent. EPA developed a relative-potency approach to estimate cancer risk associated with these PAHs by comparing PAH cancer potencies, using skin tumorogenicity bioassays, and quantifying “order of magnitude” relative potency factors (RPFs) for the six carcinogenic PAHs on the basis of comparison with the index chemical, B[a]P. This RPF approach can be used to evaluate PAH mixtures as they occur in the environment, with proportions depending on source, age of release, and environmental conditions. EPA is re- evaluating the toxicity of B[a]P and recently presented preliminary analyses in which EPA defined 26 PAHs, instead of the current six, with adequate data for RPF derivation. Dioxin-like People are exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD, or “dioxin”) and other 2,3,7,8-chlorinated EPA1987, 1989b; chemicals dioxin congeners and dioxin-like compounds as complex mixtures. Seven dioxin, 10 furan, and 12 polychlorinated Van den Berg et al. biphenyl (PCB) congeners may exert toxic effects through the same mechanism of action as 2,3,7,8-TCDD, namely, 1998, 2006 binding to the aryl hydrocarbon receptor (AhR), a cellular protein. A toxic equivalence (TEQ) approach has been developed to estimate risk associated with 2,3,7,8-TCDD and other dioxin-like congeners. The approach applies to AhR-mediated effects, assuming a model of dose addition. Each dioxin-like congener has been assigned a toxic equivalence factor (TEF) to represent the fractional toxicity of the congener relative to that of 2,3,7,8-TCDD. TEFs are used to transform concentrations of individual dioxin-like congeners into an equivalent concentration of 2,3,7,8- TCDD, as determined by the equation TEQ = + + ∑ [( Ci )( TEFi )] ∑ [( Ci )( TEFi )] ∑ [( Ci )( TEFi )] , i∈PCDDs i∈PCDFs i∈PCBs

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where TEQ = equivalent TCDD concentration, TEFi = toxic equivalency factor for congener i, and Ci = concentration of congener i. This TEQ estimate is combined with toxicity data on 2,3,7,8-TCDD to quantify risk posed by exposure to dioxin-like congener mixtures. EPA 1996a,b,c; Polychlorinated Commercial PCB mixtures released into the environment may be altered as a result of environmental processes, such EPA 1997c biphenyls as partitioning, transformation, and bioaccumulation through the food chain. Therefore, EPA recommends an approach to assess cancer risk associated with exposure to PCBs that accounts for different PCB mixtures typically found in environmental media. Cancer studies to date suggest that more highly chlorinated, less volatile congeners are associated with greater cancer risk. Those congeners tend to persist in the environment in soil and sediment and to bioaccumulate in biota. More volatile, less chlorinated congeners that partition into air or surface water are more likely to be metabolized and eliminated than highly chlorinated congeners. Therefore, EPA recommends using the environmental medium or exposure medium as an indicator of the cancer potency of a PCB mixture. For noncancer effects, EPA has developed reference doses for two commercial PCB mixtures (Aroclor 1016 and Aroclor 1254), which account for the toxicity of the mixtures but not necessarily how they might have changed after release into the environment. MADEP 2002, Petroleum The composition of petroleum products changes after release into the environment. For that reason, use of toxicity data 2003; Edwards et hydrocarbon on whole products may be appropriate for fresh spills but not for older spills that have had time to weather. al. 1997; fractions Alternatively, evaluating only a subset of individual chemicals in a mixture, such as carcinogenic PAHs and benzene, Gustafson et al. might not account for toxicity associated with the rest of the mixture. Therefore, a fraction-based approach was devised 1997 that consists of dividing petroleum mixtures into fractions and assigning physical and chemical properties and toxicity values to each fraction. This approach accounts for environmental weathering of spilled product and is a practical alternative to evaluation of hundreds of individual petroleum chemicals. Furthermore, data on toxicity and fate and transport properties needed for assessing health risk are not available for many petroleum hydrocarbons. ATSDR The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) directs ATSDR, where ATSDR 2004, interaction feasible, to develop methods for determining the health effects of substances in combination with other substances with 2007b profiles which they are commonly found. Exposure to two or more chemicals is common at hazardous-waste sites that ATSDR evaluates. Therefore, ATSDR developed a chemical-mixtures program in response to the CERCLA directive, including identification of mixtures of highest concern for pubic health and publication of final interaction profiles that evaluate toxicity data on a whole mixture, where available, and otherwise rely on mostly binary data relevant to the (Continued) 97

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98 TABLE 4-3 Continued Chemical Cumulative Risk Assessment Approach References Mixture joint toxic action of chemicals in the mixture. ATSDR has completed profiles for the following mixtures: (1) arsenic, cadmium, chromium, and lead; (2) benzene, toluene, ethylbenzene, and xylenes; (3) lead, manganese, zinc, and copper; (4) persistent chemicals found in breast milk; (5) persistent chemicals found in fish; (6) 1,1,1-trichloroethane, 1,1-dichloroethane, trichloroethylene, and tetrachloroethylene; (7) cesium, cobalt, PCBs, strontium, and trichloroethylene; (8) arsenic, hydrazines, jet fuels, strontium-90, and trichloroethylene; (9) cyanide, fluoride, nitrate, uranium; (10) atrazine, deethylatrazine, diazinon, nitrate, simazine; and (11) chlorpyrifos, lead, mercury, and methylmercury. Disinfection People are exposed simultaneously to disinfection byproducts in drinking water. EPA developed an approach to EPA 2003c; byproducts cumulative risk assessment of disinfection-byproduct mixtures that requires exposure modeling and physiologically Teuschler et al. based pharmacokinetic modeling combined with the use of cumulative relative potency factors (CRPFs). The use of 2004 CRPFs provides multiple-route, chemical-mixture risk estimates based on total absorbed doses. a Pesticides and air toxics are described in detail in text.

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99 Current Practice in Risk Assessment and Cumulative Risk Assessment No new regulatory actions were needed on the basis of EPA’s recent cu- mulative assessment of 10 N-methyl carbamate pesticides because actions taken on the basis of aggregate assessments of the individual pesticides had achieved necessary risk reductions (EPA 2008g). For example, all domestic uses of carbo- furan were deemed ineligible for reregistration, given the findings of its aggre- gate assessment. All U.S. uses of carbofuran will be canceled (EPA 2007c). National Air Toxics Assessment The National Air Toxics Assessment (NATA) is a national assessment of health risks associated with inhalation of 33 hazardous air pollutants (air toxics) and diesel particulate matter (qualitative assessment only). Assessment results are disseminated online for the public and used to inform the air-toxics program in priority-setting, air-pollution trends assessment, research, and planning (EPA 2007d). The NATA estimates concurrent exposures to the selected chemicals at the census-tract, county or state level at a selected time (EPA 2006). The cumulative methods applied for the NATA are dose addition and independent action. The common noncancer health effect of concern is respiratory irritation (irritation of the lining of the respiratory system), and single-chemical HQs of respiratory irritants are added to yield a “respiratory hazard index” (dose addition). For the carcinogens, lifetime cancer risk estimates for inhalation exposures are added (independent action but also in effect dose addition because of the assumed dose-response linearity) (EPA 2007e). More than 25 million people live in census tracts where air pollutants con- tribute to upper-bound estimates of more than 10 in 1 million increment in life- time cancer risk. The most important carcinogens that are known to contribute to the estimated excess risks are benzene and chromium (EPA 2007f). STRENGTHS AND WEAKNESSES OF CURRENT APPROACHES OR PRACTICES Having reviewed the current cumulative risk assessment practices and approaches, the committee has made the following observations: ● EPA has been addressing cumulative impact and risk under various le- gal and regulatory authorities. ● Various offices and organizations in the EPA have devoted consider- able resources to developing concepts and guidance regarding cumulative risk assessment. ● In cumulative risk assessments of human health effects, there is a reli- ance on dose addition as the default approach.

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100 Phthalates and Cumulative Risk Assessment: The Tasks Ahead ● Current practices focus on well-defined mixtures of chemical stressors to which simultaneous (or concurrent) exposures occur. In its Framework for Cumulative Risk Assessment (EPA 2003b), EPA has developed an appropriately broad definition of cumulative risk assessment and identified multiple approaches to the conduct of such assessments. EPA, through its various offices, has accrued substantial practical experience with cumulative risk assessment. However, the assessments conducted to date have been of well- defined groups of chemicals to which simultaneous exposure occurs. Chemicals are grouped according to a common mechanism of toxic action or end point and specific exposure situations, such as a hazardous-waste site or spill or presence in food or water. Therefore, although multiple methods are available, EPA has used only a few of them in practice. And despite recognition of nonchemical stressors as potentially important contributors to cumulative risk, nonchemical stressors are rarely addressed or evaluated. APPLICATION TO PHTHALATES EPA clearly has given considerable thought to cumulative risk assessment and has produced substantial guidance on it. On the basis of that guidance, a mixture of phthalates should be included in a cumulative assessment based on “toxicologic similarity” (see Chapter 3). However, there may be inconsistencies in how different offices in EPA would perform risk assessments, the available IRIS toxicity values do not incorporate the relevant end points that would sug- gest toxicologic similarity, and some of the guidance is pulling in different di- rections in that toxicologic similarity is largely undefined. A sufficiently de- tailed examination of the toxicologic profiles and mechanisms of action of the individual phthalates would find distinct differences in end points affected or the degree to which specific end points are affected and in detailed mechanisms of action, so toxicologic similarity would be ambiguous. The following chapter examines the evaluation of phthalate mixtures in more detail and provides practical approaches to the examination of phthalates mixtures in particular and other mixtures in general. REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 2004. Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Sub- stances and Disease Registry. May 2004 [online]. Available: http://www.atsdr. cdc.gov/interactionprofiles/ipga.html [accessed July 22, 2008]. ATSDR (Agency for Toxic Substances and Disease Registry). 2007a. Minimum Risk Levels (MRLs) for Hazardous Substances, November 2007 [online]. Available: http://www.atsdr.cdc.gov/mrls/ [accessed June 16, 2008].

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101 Current Practice in Risk Assessment and Cumulative Risk Assessment ATSDR (Agency for Toxic Substances and Disease Registry). 2007b. Final Interaction Profiles [online]. Availble: http://www.atsdr.cdc.gov/interactionprofiles/ [accessed June 16, 2008]. Berenbaum, M.C. 1985. The expected effect of a combination of agents: The general solution. J. Theor. Biol. 114(3):413-431. Berenbaum, M.C. 1989. What is synergy? Pharmacol. Rev. 41(2):93-141. Carlson-Lynch, H., J. Stickney, P. McClure, M. Gehlhaus, and L. Flowers. 2007. Pro- posed Derivation of Relative Potency Factors (RPFs) for Individual Polycyclic Aromatic Hydrocarbons and Characterization of Uncertainty. Abstract M3-E5. Presented at the Society for Risk Analysis Annual Meeting 2007-Risk 007: Agents of Analysis, December 9-12, 2007, San Antonio, TX [online]. Available: http://birenheide.com/sra/2007AM/program/singlesession.php3?sessid=M3-E [ac- cessed July 15, 2008]. Edwards, D.A., M.D. Andriot, M.A. Amoruso, A.C. Tummey, C.J. Bevan, A. Tveit, L.A. Hayes, S.H. Youngren, and D.V. Nakles. 1997. Development of Fraction Specific Reference Doses (RfDs) and Reference Concentrations (RfCs) for Total Petroleum Hydrocarbons (TPH). Total Petroleum Hydrocarbon Criteria Working Group Se- ries, Vol. 4. Amherst, MA: Amherst Scientific Publishers [online]. Available: http://www.aehs.com/publications/catalog/contents/Volume4.pdf [accessed July 23, 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 [on- line]. Available: http://www.epa.gov/ncea/raf/pdfs/chem_mix/chemmix_1986.pdf [accessed July 23, 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. March 1987. EPA (U.S. Environmental Protection Agency). 1989a. Risk Assessment Guidance for Superfund, Volume I. Human Health Evaluation Manual (Part A). Interim Final. EPA/540/1-89/002. PB90-155581. Office of Emergency and Remedial Response, U.S. Environmental Protection Agency, Washington, DC. December 1989 [online]. Available: http://rais.ornl.gov/homepage/HHEMA.pdf [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 1989b. 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. EPA (U.S. Environmental Protection Agency). 1992. Guidelines for Exposure Assess- ment. EPA/600/Z-92/001. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. May 1992 [online]. Available: http://rais.ornl.gov/ homepage/GUIDELINES_EXPOSURE_ASSESSMENT.pdf [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 1993a. Use of IRIS Values in Superfund Risk Assessment. OSWER Directive 9285.7-16. Memorandum to Directors, Waste Management Division Region I, IV, VII, VIII, Director, Emergency and Remedial Response Division Region II, Directors, Hazardous Waste Management Division

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102 Phthalates and Cumulative Risk Assessment: The Tasks Ahead Regions III, VI, IX, and Directors, Hazardous Waste Division, Region X, from William H. Farland, Director, Office of Health and Environmental Assessment, Henry L. Longest II, Director, Office of Emergency and Remedial Response, U.S Environmental Protection Agency, Washington, DC. December 21, 1993 [online]. Available http://www.epa.gov/oswer/riskassessment/pdf/irismemo.pdf [accessed May 13, 2008]. EPA (U.S. Environmental Protection Agency). 1993b. Provisional Guidance for Quanti- tative 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/risk assessment/pdf/1993_epa_600_r-93_c89.pdf [accessed June 10, 2008]. EPA (U.S. Environmental Protection Agency). 1996a. Aroclor 1016 (CASRN 12674-11- 2). Integrated Risk Information System, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/ncea/iris/subst/0462.htm [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 1996b. Aroclor 1254 (CASRN 11097-69- 1). Integrated Risk Information System, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/ncea/iris/subst/0389.htm [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 1996c. PCBs: Cancer Dose-Response Assessment and Application to Environmental Mixtures. EPA/600/P-96/001F. Na- tional Center for Environmental Assessment, Office of Research and Develop- ment, U.S. Environmental Protection Agency, Washington, DC. September 1996 [online]. Available: http://www.epa.gov/pcb/pubs/pcb.pdf [accessed June 10, 2008]. EPA (U.S. Environmental Protection Agency). 1997a. Cumulative Risk Assessment Guidance-Phase I Planning and Scoping. Memorandum to Assistant Administra- tors, General Counsel, Inspector General, Associate Administrators, Regional Ad- ministrators, Staff Office Directors, from Carol M. Browner, Administrator, and Fred Hansen, Deputy Administrator, U.S. Environmental Protection Agency. July 3, 1997 [online]. Available: http://www.epa.gov/OSA/spc/pdfs/cumulrisk.pdf [ac- cessed July 23, 2008]. EPA (U.S. Environmental Protection Agency). 1997b. Guidance on Cumulative Risk Assessment. Part 1. Planning and Scoping. Science Policy Council, U.S. Environ- mental Protection Agency, Washington, DC. July 3, 1997 [online]. Available: http://www.epa.gov/OSA/spc/pdfs/cumrisk2.pdf [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 1997c. Polychlorinated Biphenyls (PCBs) (CASRN 1336-36-3). Integrated Risk Information System, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/ncea/iris/subst/ 0294.htm [accessed July 22, 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). 2001. Risk Assessment Guidance for Superfund, Volume 3- Part A: Process for Conducting Probabilistic Risk Assess- ment. EPA 540-R-02-002. Office of Emergency and Remedial Response, U.S. En- vironmental Protection Agency, Washington, DC. December 2001 [online]. Avail- able: http://www.epa.gov/oswer/riskassessment/rags3adt/ [accessed July 22, 2008].

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103 Current Practice in Risk Assessment and Cumulative Risk Assessment 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). 2003a. Human Health Toxicity Values in Superfund Risk Assessments. OSWER Directive 9285.7-53. Memorandum to Superfund National Policy Managers, Regions 1 - 10, from Michael B. Cook, Di- rector, Office of Superfund Remediation and Technology Innovation, Washington, DC. December 5, 2003 [online]. Available: http://www.epa.gov/oswer/riskassess ment/pdf/hhmemo.pdf [accessed May 13, 2008]. EPA (U.S. Environmental Protection Agency). 2003b. Framework for Cumulative Risk Assessment. EPA/630/P-02/001F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. May 2003 [online]. Available: http://oaspub. epa.gov/eims/eimscomm.getfile?p_download_id=36941 [accessed June 10, 2008]. EPA (U.S. Environmental Protection Agency). 2003c. The Feasibility of Performing Cumulative Risk Assessments for Mixtures of Disinfection By-Products in Drink- ing Water. EPA/600/R-03/051. National Center for Environmental Assessment, U.S. Environmental Protection Agency, Cincinnati, OH. June 2003 [online]. Available: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=56834 [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 2005a. Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. March 2005 [online]. Available: http://cfpub. epa.gov/ncea/cfm/recordisplay.cfm?deid=116283 [accessed Sept. 2, 2008]. EPA (U.S. Environmental Protection Agency). 2005b. Supplemental Guidance for As- sessing Susceptibility from Early-Life Exposure to Carcinogens. EPA/630/R- 03/03F. Risk Assessment Forum, U.S. Environmental Protection Agency, Wash- ington, DC. March 2005 [online]. Available: http://www.epa.gov/iris/children 032505.pdf [accessed June 16, 2008). EPA (U.S. Environmental Protection Agency). 2006. 1996 National Air Toxics Assess- ment Exposure and Risk Data. Technology Transfer Network National Air Toxics Assessment, U.S. Environmental Protection Agency [online]. Available: http:// www.epa.gov/ttn/atw/nata/ted/exporisk.html [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 2007a. 1,1,1-Trichloroethane (CASRN 71-55-6). Integrated Risk Information System, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/ncea/iris/subst/0197.htm [ac- cessed July 23, 2008]. EPA (U.S. Environmental Protection Agency). 2007b. Provisional Peer Reviewed Toxic- ity Values for Dimethyl Phthalate (CASRN 131-11-3). Superfund Health Risk Technical Support Center, National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Cincinnati, OH. September 25, 2007. EPA (U.S. Environmental Protection Agency). 2007c. Risk Management Decisions for Individual N-methyl Carbamate Pesticides. Pesticides, U.S. Environmental Protec- tion Agency [online]. Available: http://www.epa.gov/pesticides/cumulative/ carbamate_risk_mgmt.htm [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 2007d. 1996 National-Scale Air Toxics Assessment. Overview: EPA’s Use of Results. Technology Transfer Network, U.S.

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104 Phthalates and Cumulative Risk Assessment: The Tasks Ahead Environmental Protection Agency [online]. Available: http://www.epa.gov/ttn/ atw/nata/ur.html [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 2007e. 1996 National-Scale Air Toxics Assessment. Background on Risk Characterization. Technology Transfer Network, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/ ttn/atw/nata/riskbg.html [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 2007f. 1996 National-Scale Air Toxics Assessment. Summary of Results. Technology Transfer Network, U.S. Environ- mental Protection Agency [online]. Available: http://www.epa.gov/ttn/atw/ nata/risksum.html [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 2007g. 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]. EPA (U.S. Environmental Protection Agency). 2008a. Target Compounds and Analytes. Superfund Analytical Services/Contact Laboratory Program, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/superfund/programs/ clp/target.htm [accessed July 23, 2008]. EPA (U.S. Environmental Protection Agency). 2008b. IRIS Glossary. Integrated Risk Information System (IRIS), U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/ncea/iris/help_gloss.htm#r [accessed July 23, 2008]. EPA (U.S. Environmental Protection Agency). 2008c. EPA’s Integrated Risk Information System: Assessment Development Procedures. IRIS Process (2008 Update). Na- tional Center for Environmental Assessment, U.S. Environmental Protection Agency. April 2008 [online]. Available: http://cfpub.epa.gov/ncea/cfm/record isplay.cfm?deid=190045 [accessed June 11, 2008]. EPA (U.S. Environmental Protection Agency). 2008d. Assessing Pesticide Cumulative Risk. Pesticides, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/pesticides/cumulative/index.htm [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 2008e. Common Mechanism Groups; Cumulative Exposure and Risk Assessment. Pesticides, U.S. Environmental Pro- tection Agency [online]. Available: http://www.epa.gov/pesticides/cumulative/ common_mech_groups.htm [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 2008f. Proposed Approach for Estimation of Bin-Specific Cancer Potency Factors for Inhalation Exposure to Asbestos. Of- fice of Solid Waste and Emergency Response, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/oswer/riskassessment/asbestos/ pdfs/2008_prop_asbestos_approach.pdf [accessed July 22, 2008]. EPA (U.S. Environmental Protection Agency). 2008g. Revised N-Methyl Carbamate Cumulative Risk Assessment. Office of Pesticide Programs, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/pesticides/cumulative/ common_mech_groups.htm#carbamate [accessed July 22, 2008]. Gustafson, J.B., J.G. Tell, and D. Orem. 1997. Selection of Representative TPH fractions Based on Fate and Transport Considerations. Total Petroleum Hydrocarbon Crite- ria Working Group Series, Vol. 3. Amherst, MA: Amherst Scientific Publishers

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