Phthalates and Cumulative Risk Assessment The Tasks Ahead (2008) / Chapter Skim
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4 Current Practice in Risk Assessment and Cumulative Risk Assessment
4 Current Practice in Risk Assessment and Cumulative Risk Assessment
Pages 68-105
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From page 68... ...
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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From page 69... ...
web site -- the application of the toxicity assessments typically differs considerably between the two. Sitespecific risk assessments are often concerned with simultaneous evaluation of multiple chemicals, multiple pathways of exposure, multiple routes of exposure, and multiple receptors.
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From page 70... ...
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 degree.
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From page 71... ...
Toxicity Assessment As in the preceding section, this section provides an idealized general description, not a critical review, of the current practice of toxicity assessment. General Approach The practical and most commonly adopted approach to toxicity assessment in EPA risk assessments is to obtain toxicity values from the EPA IRIS database for chronic oral reference doses (RfDs)
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From page 72... ...
In some cases, such as that of vinyl chloride, 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)
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From page 73... ...
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.
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From page 74... ...
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)
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From page 75... ...
subchronic-to-chronic oral study: increased mortality Low confidence (8/1/1990) EPA contractor updated review (11/2001)
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Critical effects from 6-mo rat mononuclear cell leukemia feeding study: significantly response do not provide a increased liver-to-body weight compelling basis to model the and liver-to-brain weight ratios dose-response data," EPA contractor updated review Low confidence (2/1/1993)
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From page 77... ...
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.
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From page 78... ...
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 timeframes of exposure.
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From page 79... ...
To define dose addition precisely in the general case, consider a mixture with doses dA of component A, dB of component B, dC of component C, and so on; this mixture produces level E of some specific effect. Suppose that the doses of the individual components that each acting alone produce level E of the same specific effect are DA, DB, DC..., where these values are set to infinity if that component does not produce the specific effect at any dose (the case of nonmonotonic dose-response relationships is not considered here but does not present any great difficulties)
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From page 80... ...
Reprinted with permission; copyright 1988, Archives Internationales De Pharmacodynamie. The statement defining dose addition says nothing about the shapes of the dose-response curves for the individual components, and nothing can be adduced about the dose additivity or non-dose additivity of a mixture from the shapes of the dose-response curves of its components (undocumented statements to the contrary in EPA 2000, Section 4.2.2 and Table B-1, notwithstanding)
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From page 81... ...
Figure 4-1 provides a striking example of such a situation for a twocomponent mixture. ● Second, conclusions about dose addition, synergism, or antagonism or more generally about the shape of an isobole may not be the same for different levels of effect even for similar mixture ratios -- geometrically, isoboles are not necessarily parallel.
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From page 82... ...
, but it is quite adequate for its typical use of combining small effects where the product term is negligible. Equations 4 and their generalizations to multiple agents define independent action in the same way that Equation 1 defines dose addition.
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From page 83... ...
independent action and noninteraction are assumed to be equivalent, or when synergism and antagonism are defined by deviations from one and inappropriately compared with identical terms defined by deviations from the other. Empirical Observation vs Mechanistic Inference With the assumption of dose addition or independent action, the doseresponse relationship of a mixture of components may be calculated on the basis of dose-response relationships observed for mixture components.
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From page 84... ...
84 Phthalates and Cumulative Risk Assessment: The Tasks Ahead BOX 4-3 Hypothetical Example Represented in Figure 4-2 Consider a chemical applied at dose rate d to an organism that has an elimination rate for that chemical that is of Michaelis-Menten form. The concentration C in some target tissue at steady state will then satisfy an equation of the form λC d = , k +C where λ is the maximum elimination rate (so consider dose rates less than λ)
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From page 85... ...
It is generally convenient in performing such evaluations to compare observations against dose addition or independent action, and if the deviations are small enough to be statistically insignificant the mixtures may be considered to exhibit dose addition or independent action for that particular effect at that effect level (many examples of both kinds are known; see Berenbaum 1989 for an extensive review)
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From page 86... ...
An even more restrictive application of dose addition may be proposed and used in practice, as it has been for the 2,3,7,8-chlorinated dibenzo-p-dioxins and -furans and for "dioxin-like" PCB congeners (Van den Berg et al.
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From page 87... ...
If shorter-term RfD or RfC values (or equivalents from the hierarchic selection of toxicity values) are not available, RfD and RfC values from longer-term exposures may be used for shorter-term exposures, and the resulting HQs are considered likely to be conservative (overestimates)
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From page 88... ...
for each chemical. Thus, under the hypothesis of dose addition, if the HI is less than or equal to unity, no effect can be expected from the mixture of chemicals incorporated in the summation.
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From page 89... ...
Special Considerations in Practical Risk Characterizations As pointed out above, some groups of chemicals are treated specially by using relative-potency or TEF approaches; these are discussed further in the section "Current EPA Cumulative Risk Assessment Examples and Case Studies" below. Some mixtures, such as Aroclors (PCB mixtures)
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From page 90... ...
At times, that proved difficult because there may be more than one statement or definition, and the default approach may not have been explicitly stated. The "Default approach" column of the table highlights some statements made in the guidance about the conditions required for dose addition or independent action.
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From page 91... ...
1) if the compounds do not have the same mode Assessment Forum, also of toxicologic action," and the published 51FR34014-34025 recommendation was that "depending on the nature of the risk assessment and the available information on modes of action and patterns of joint action, the … most reasonable additive model should be used." (Dose addition and independent action are the only alternatives discussed.)
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From page 92... ...
2) A Framework for Cumulative "The goal of this project is to develop a Implicitly examined only multiple No default is specified, although the text may Risk Assessment, ILSI Risk framework that can be used to guide the chemical exposures imply some sort of unspecified additivity at Science Institute Workshop conduct of cumulative risk assessments." low dose.
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ii) to as cumulative risk assessment." CMG implies dose addition for its member (EPA 2002, p.
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From page 94... ...
EPA/600/R- regulatory document and is not guidance stressors may include chemicals, as 06/013F, August 2007, EPA, but rather a presentation of concepts, well as biological or physical agents National Center for methods and data sources." (EPA 2007g, (e.g., noise, nutritional status) , or the Environmental Assessment, p.
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From page 95... ...
. 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.
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From page 96... ...
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)
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From page 97... ...
Polychlorinated Commercial PCB mixtures released into the environment may be altered as a result of environmental processes, such EPA 1996a,b,c; biphenyls as partitioning, transformation, and bioaccumulation through the food chain. Therefore, EPA recommends an approach EPA 1997c to assess cancer risk associated with exposure to PCBs that accounts for different PCB mixtures typically found in environmental media.
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From page 98... ...
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)
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From page 99... ...
. 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)
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From page 100... ...
. 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 suggest toxicologic similarity, and some of the guidance is pulling in different directions in that toxicologic similarity is largely undefined.
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From page 101... ...
1986. Guidelines for the Health Risk As sessment of Chemical Mixtures.
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From page 102... ...
2000. Supplementary Guidance for Con ducting Health Risk Assessment of Chemical Mixtures.
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2003a. Human Health Toxicity Values in Superfund Risk Assessments.
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From page 104... ...
2007g. Concepts, Methods, and Data Sources for Cumulative Health Risk Assessment of Multiple Chemicals, Expo sures and Effects: A Resource Document.
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From page 105... ...
2003. Updated Petro leum Hydrocarbon Fraction Toxicity Values for the VPH/EPH/APH Methodology.
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