PHTHALATES AND CUMULATIVE RISK ASSESSMENT


The Tasks Ahead



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Summary People are exposed to a great variety of chemicals throughout their daily lives in the foods they eat, in the air they breathe, and in the water they drink. Some exposures, such as to natural components of foods, are clearly intentional, and others are inadvertent. Over the last few decades, the U.S. Environmental Protection Agency (EPA) has been developing guidance to evaluate the cumula- tive risk posed by multiple chemical exposures and other stressors that can mod- ify the effects of specific chemical exposures. Recent guidance has tended to focus on chemicals that are structurally related, such as organophosphate pesti- cides, on the assumption that such chemicals have a common mechanism of action. Phthalate esters constitute a chemical class about which concern has emerged. Phthalates are used in a wide variety of consumer products, including cosmetics, personal-care products, pharmaceuticals, medical devices, children’s toys, food packaging, and cleaning and building materials. Recent studies show widespread human exposure to multiple phthalates and indicate that effects on the development of the reproductive system of laboratory animals occur at much lower doses than were predicted in earlier studies. The European Union and the United States have passed legislation that restricts the concentrations of several phthalates in children’s toys, and the European Union has banned several phthal- ates from cosmetics. In this context, EPA asked the National Research Council to review independently the health effects of phthalates, determine whether cu- mulative risk assessment of this chemical class should be conducted, and, if so, indicate approaches that could be used for the assessment. The applicability of such approaches to other chemical classes and to cumulative risk assessment generally was also to be considered. In response to EPA’s request, the National Research Council convened the Committee on the Health Risks of Phthalates, which prepared this report. To address its task, the committee reviewed scientific literature on phthal- ates and the effects of chemical mixtures, reviewed guidance and other docu- ments on cumulative risk assessment, and heard presentations by experts in the 3

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4 Phthalates and Cumulative Risk Assessment: The Tasks Ahead fields of phthalate toxicity and cumulative risk. The committee found that the definition of cumulative risk assessment has evolved over the years but agreed with recent publications that define cumulative risk broadly to mean the risk posed by multiple chemicals and other stressors that cause varied health effects and to which people are exposed by multiple pathways and exposure routes and for varied durations. This report is not a comprehensive toxicologic profile or risk assessment of any particular phthalate or of the chemical class as a whole. Rather, it answers two questions: Should cumulative risk assessment of phthalates be conducted? If so, how should the assessment be conducted? The committee considered primar- ily the most sensitive health outcomes resulting from exposure to phthalates (effects on the development of the male reproductive system) as an illustrative example for cumulative risk assessment. The committee’s suggestions should not be interpreted to imply that other health effects are not important or that nonchemical stressors should be ignored. MODE OF ACTION, MECHANISM OF ACTION, AND COMMON ADVERSE OUTCOMES Mode of action and mechanism of action are terms that are commonly used in risk assessment and often used interchangeably. Both refer to the bio- logic pathway to some final health outcome; the difference between the terms is the level of detail used to describe the pathway. Typically, mechanism of action is used to describe the pathway at the molecular level, and mode of action is used to describe the key events along the pathway. Although the committee rec- ognizes the distinction and does not want to contribute to greater confusion con- cerning the use of the terms, mechanism of action is used in this report to de- scribe the biologic pathway. In recent years, the focus in cumulative risk assessment has been on chemicals that have common mechanisms of action. As described below and in greater detail in this report, the committee finds that the focus in cumulative risk assessment should be on the health outcomes and not on the pathways that lead to them, whether defined as mechanisms of action or as modes of action. Multi- ple pathways can lead to a common outcome, and a focus on only a specific pathway can lead to too narrow an approach in conducting a cumulative risk assessment. Accordingly, the chemicals that should be considered for cumula- tive risk assessment should be ones that cause the same health outcomes or the same types of health outcomes, such as a specific set of effects on male repro- ductive development, not ones that cause the health outcomes only by a specific pathway. The committee refers to the health outcomes of interest as common adverse outcomes.

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5 Summary WHY A CUMULATIVE RISK ASSESSMENT? Answering two basic questions helps to determine whether a cumulative risk assessment of phthalates is warranted. First, are there exposures to multiple phthalates? Second, do the exposures contribute to common adverse outcomes? There is clearly potential for exposures because phthalates occur in a wide vari- ety of consumer products, including toys, cosmetics, pharmaceuticals, and build- ing and construction materials. Furthermore, the National Health and Nutrition Examination Survey (NHANES) conducted by the Centers for Disease Control and Prevention has documented simultaneous exposure to multiple phthalates in the general population, including children and adults. Other studies support those findings. An important finding of the surveys is that concentrations of phthalate metabolites in urine are generally higher in children than adults; the differences may result from differences in exposure or from possible differences in metabolism between children and adults. The metabolic differences are im- portant because they may alter the risk posed by exposure; that is, they may make one person more or less susceptible than another to the effects of phthal- ates. Other studies have shown that phthalates cross the placenta, and multiple phthalates have been measured in animal and human amniotic fluid. On the ba- sis of the exposure surveys and studies, the first question—whether there is ex- posure to multiple phthalates—has been answered affirmatively. Not only con- current exposure, but concurrent exposure at all life stages, has been demon- strated. The second question concerns whether exposures to multiple phthalates contribute to common adverse outcomes. Few human data on the health effects of phthalate exposure are available. Most data are from laboratory studies of rats, which have been shown to be the most phthalate-sensitive of the species tested. Early studies indicated that hepatic cancer and teratogenic effects could be induced if high doses were administered long enough or during a specific time. However, the protocol of the early teratology studies required dosing pregnant animals from gestation day 6 to 15 (the major period of organogene- sis). In the late 1990s, it became evident that chemicals could affect sexual dif- ferentiation, which occurs during gestation days 12-21 in rats. Thus, the early protocol did not expose animals throughout the critical developmental window. The time when the animals were evaluated also posed a problem. The standard teratology protocol requires that fetuses be examined just before term; however, the malformations characteristic of phthalate exposure would be difficult or im- possible to diagnose without a detailed histopathologic examination, which is not required by current guidelines. If the protocol is modified to include expo- sure during the critical window and the animals are examined postnatally, a va- riety of effects on the development of the reproductive system can be observed in males at much lower doses than previously observed after exposure to various phthalates. That group of effects observed in male animals is known as the

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6 Phthalates and Cumulative Risk Assessment: The Tasks Ahead phthalate syndrome and includes 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. Those effects are characteristic more generally of distur- bance of androgen1 action. Furthermore, the phthalate syndrome has many simi- larities to the hypothesized testicular dysgenesis syndrome in humans, although there are no human data that directly link the hypothesized syndrome with phthalate exposure. Figure S-1 shows the relationship between the various syndromes and il- lustrates the range of common effects on the development of the male reproduc- tive system. The committee concludes that the second question—about common adverse outcomes of phthalates—has been answered affirmatively. However, the committee emphasizes that not all phthalates are equivalent in the severity of their effects. The phthalates that are most potent in causing effects on the devel- opment of the male reproductive system are generally those with ester chains of four to six carbon atoms; phthalates with shorter or longer chains typically ex- hibit less severe or no effects. Furthermore, the age of the animals at the time of Human Testicular Phthalate Syndrome Dysgenesis Syndrome Disturbance of Androgen Action Fetal Germ- Testicular Germ- Hypospadias Cell Effects Cell Cancer Cryptorchidism Other reproductive tract malformations ↓LC function, [↑Tumors] ↓AGD, [Nipple retention] ↓Fertility ↓insl3 Gubernacular malformations FIGURE S-1 Relationship of phthalate syndrome in rats to effects associated with agents that perturb androgen action and produce androgen insufficiency and to the hypothesized testicular dysgenesis syndrome in humans. Outcomes in brackets are restricted to findings in experimental animals. AGD, anogenital distance; insl3, insulin-like factor 3; LC, Ley- dig cell; ↑, increase; and ↓, decrease. 1 Androgen is a generic term for male sex hormone. The primary androgen is testoster- one.

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7 Summary exposure is critical with respect to the severity of the effects; the fetus is the most sensitive life stage. Studies indicate that some phthalates reduce testosterone concentrations; this androgen insufficiency causes the variety of effects observed if it occurs at times that are critical for male reproductive development. That point is impor- tant in considering cumulative risk assessment because a number of other agents (often referred to as antiandrogens) can produce similar effects through pertur- bations in androgen concentrations or in androgen-receptor signaling. In repro- ductive tissues that require androgen for normal development, it is unlikely that one can differentiate between a decreased concentration of androgen and an- tagonism of androgen-receptor signaling; the responses would be similar. Thus, any agent that can produce androgen insufficiency or block androgen-receptor signaling in the developing male fetus would have effects that are included in the array of malformations known to be caused by phthalates. On the basis of the findings summarized above, the committee recom- mends that a cumulative risk assessment be conducted for phthalates and that the assessment include other antiandrogens, as described further in the next section. CONSIDERATIONS FOR CONDUCTING CUMULATIVE RISK ASSESSMENT One approach to cumulative risk assessment of a mixture is to consider the mixture as a single agent and develop toxicity data on the mixture. That ap- proach has been used for some industrial products, such as commercial mixtures of polychlorinated biphenyls, and industrial waste streams, such as coke-oven emissions. However, such an approach assumes that the composition of the mix- ture does not change and that the components always occur together. Because the components and concentrations of phthalate mixtures are likely to vary, the whole-mixture approach is not appropriate for phthalates. Another approach is to explain the effects of a mixture in terms of the in- dividual components (that is, a component-based approach). When chemicals in a mixture act together to produce an effect and do not enhance or diminish each other’s actions, the outcome of exposure to the mixture is considered additive. Two distinct concepts—dose addition and independent action2—have been used as models to describe and estimate ideal additive mixture effects, although other approaches have been introduced, and the literature can be confusing and may often appear contradictory. Dose addition arises if the “dilution” principle ap- plies, so that one chemical can be replaced with a fraction of an equally effective concentration of another chemical without changing the overall combined effect. Independent action is based on the idea of, and may arise from, statistically in- dependent action of each component. Mixtures may demonstrate effects larger than expected (synergism) or smaller than expected (antagonism), although the 2 Independent action is also referred to as response addition.

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8 Phthalates and Cumulative Risk Assessment: The Tasks Ahead determination of synergism or antagonism may depend on the model chosen for comparison. There are marked differences between the chemical-by-chemical approach to risk assessment and evaluations that take mixture effects into account. Where single-chemical risk assessments might yield the verdict “absence of risk,” dose addition might yield the opposite conclusion. Specifically, there is an expecta- tion with dose addition that every component at any dose contributes, in propor- tion to its prevalence, to the overall mixture toxicity. Whether the individual doses of mixture components are effective on their own does not matter. For example, let a dose of 4 × 10-2 arbitrary dose units produce an effect of measur- able magnitude (see Figure S-2). The same effect will be obtained when the chemical is administered in 10 simultaneous portions of 4 × 10-3 dose units, even though the response to each one of those dose fractions is not measurable. If dose addition applies, the same holds when 10 portions of 10 chemicals with identical response curves are used. Thus, combined effects should also result from chemicals at doses associated with no measurable effect or “zero” effect, provided that sufficiently large numbers of components sum to a suitably high effect dose. The situation described here for dose addition may not be the case with independent action because responses are viewed “independently” of each other, and summing “zero” effects of the individual components would lead to a 1.8 1.6 1.4 Effect (arbitrary scale) 1.2 1.0 0.8 2 0.6 1 0.4 0.2 0.0 10 -3 10 -2 10 -1 10 0 Dose (arbitrary units) FIGURE S-2 Illustration of a hypothetical mixture experiment with chemicals that all exhibit the same dose-response curve. At the low dose to the left (arrow 1, 4 × 10-3 dose units), the effect is hardly observable. A combination of 10 agents at that dose (arrow 2, total dose, 4 × 10-2 dose units) produces a significant combined effect consistent with expectations based on dose addition.

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9 Summary prediction of a “zero” mixture effect. However, that proposition forces clear distinctions between “zero” effects and small effects that are beyond the resolv- ing power of experimental studies. Particularly in the case of mixtures of large numbers of components, small, albeit statistically insignificant responses may sum to considerable mixture effects, even when independent action applies. Various EPA programs and offices have developed cumulative-risk- assessment definitions and approaches that are specific to their regulatory or statutory needs, although early guidance focused on dose-addition methods as a default, at least for chemicals that affect a given organ system. Recent EPA guidance has asserted that if dose-addition methods are to be used, the chemicals for consideration should exhibit the same mechanism of action. However, it can be difficult to define criteria for determining similar mechanisms of action. Some might say that chemicals that produce similar responses have the same mechanism of action, and others might require that data show that chemicals act through identical molecular pathways and thus produce exactly the same inter- mediates at each step in the pathway. The latter requirement would result in con- sideration of few chemicals for any cumulative risk assessment. EPA also stipu- lates in recent guidance documents that dose-response curves of the chemicals should be parallel if dose-addition methods are to be used. The committee concluded that EPA’s more recent stipulations on when dose-addition methods should be used are too restrictive. Phthalates may not all act by the same mechanisms, and they do not have parallel dose-response curves. However, those facts do not negate the appropriateness of using general dose-addition methods in a cumulative risk assessment. The committee empha- sizes that parallel dose-response curves are not required for dose-addition meth- ods generally, although they may be required for some specific applications, such as some relative-potency approaches. The stipulations that EPA has placed on using dose-addition methods raise a greater issue. The stipulations have affected how EPA evaluates chemicals for cumulative risk assessment, for example, grouping structurally related chemicals on the assumption that they act by the same mechanisms. For cumulative risk assessment, the committee strongly recommends that EPA group chemicals that cause common adverse outcomes and not focus exclusively on structural simi- larity or on similar mechanisms of action. Accordingly, phthalates and other agents that cause androgen insufficiency or block androgen-receptor signaling, and are thus capable of inducing effects that characterize components of the phthalate syndrome, should be considered in a cumulative risk assessment. A focus solely on phthalates to the exclusion of other antiandrogens would be arti- ficial and could seriously underestimate cumulative risk. The question then becomes whether dose addition, independent action, or some other method is the most appropriate for estimating risk associated with phthalates and other antiandrogens. The committee concludes that the answer should be based on empirical data that directly test any proposed method. Mix- ture studies in laboratory animals have been conducted with phthalates, with other antiandrogens, and with phthalates and other antiandrogens; the results all

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10 Phthalates and Cumulative Risk Assessment: The Tasks Ahead indicate that the mixture effects in each case are predicted well with dose- addition methods. Although a variety of mechanisms clearly are involved, dose addition proved adequately predictive when the committee evaluated the avail- able data. More important, when the model predictions differed significantly, no case could be found in which independent action predicted mixture effects better than dose addition. Thus, the evidence supports the use of dose addition as an approximation in estimating cumulative risk posed by phthalates and other antiandrogens. The use of a dose-addition model is also supported by data that show cumulative effects at doses at which individual mixture components did not induce observable effects. There are several approaches for conducting cumulative risk assessment with the dose-addition approach. This report outlines a few possible options, ranging from the relatively straightforward, focusing on one particular outcome, to the more complex, involving the development of a composite score for a vari- ety of outcomes. Each option will have advantages and disadvantages, and EPA should evaluate each option and determine which is most appropriate. The committee emphasizes that the conceptual approach taken for phthalates should be applicable to other agents. FUTURE DIRECTIONS The current practice of restricting cumulative risk assessment to structur- ally or mechanistically related chemicals ignores the important fact that different chemical exposures may result in the same common adverse outcomes. Focus- ing primarily on physiologic consequences rather than structural or mechanistic similarity is a critical and achievable next step in cumulative risk assessment and is more directly relevant to relating chemical exposures to human diseases and disorders. Accordingly, the cumulative risk assessment of phthalates should consider any chemical that leads to disturbance of androgen action and is thus capable of inducing any of the effects on the development of the male reproduc- tive system that are characteristic of phthalate exposure (see Figure S-3). Which chemicals to include in the cumulative risk assessment will depend on whether there is a potential for exposure in which the chemicals would exhibit common adverse outcomes. The committee emphasizes that its recommendation to focus on common adverse outcomes in cumulative risk assessment does not mean that information on mechanism of action is not desirable. That information is useful for defining critical pathways and system-level physiology, for determining the relevance of effects observed in animals to humans, and for reducing uncertainty in determining risk. On the basis of its review, the committee concludes that sufficient data are available to proceed with the cumulative risk assessment of phthalates and other antiandrogens. However, addressing current data gaps would lead to greater refinement of a cumulative risk assessment and reduce uncertainty associated

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11 Summary Antiandrogenic compounds , P hthalates other ris k factors D is turbed androgen action Altered male reproductive outcomes FIGURE S-3 Multiple exposures leading to common adverse outcomes. with any risk estimates. Because issues surrounding fetal exposure are particu- larly important in phthalate risk assessment, research to determine prenatal ex- posure to phthalates at multiple relevant times during pregnancy is critical. It is especially important to determine whether metabolite concentrations in the fetal compartment vary during pregnancy; if they do, it would indicate possible meta- bolic differences at different gestational ages. More generally, the full spectrum of phthalate metabolites needs to be characterized, the most appropriate metabo- lites to use as biomarkers of human exposure need to be determined, and the most important sources of phthalate exposure in the general population need to be identified. Because differences in susceptibility clearly depend on age, spe- cies, and exposure route, research to understand why the differences occur is important. Finally, research is needed to investigate possible deviations from the dose-addition concept—that is, identification of cases of synergism or antago- nism relative to dose addition. The committee recognizes that its recommendation to move beyond the constraints of structural or mechanistic similarity for cumulative risk assessment may appear challenging. One might ask, “With so many chemicals, where do we begin?” However, the committee concludes that it is plausible and warranted to extend cumulative risk assessment to include chemicals associated with com- mon adverse outcomes as exemplified in this report by inclusion of other antian- drogenic chemicals with phthalates. To cite another example, EPA could evalu- ate combined exposures to lead, methylmercury, and polychlorinated biphenyls because all contribute to cumulative risk of cognitive deficits consistent with IQ reduction in children, although the deficits are produced by different mecha- nisms of action. Cumulative risk assessment based on common adverse out- comes is a feasible and physiologically relevant approach to the evaluation of the multiplicity of human exposures and directly reflects EPA’s mission to pro-

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12 Phthalates and Cumulative Risk Assessment: The Tasks Ahead tect human health. Such a shift in approach would entail substantial efforts by EPA, such as those required to define and set priorities among the most impor- tant adverse health outcomes. However, a focus on common adverse outcomes actually facilitates the process by defining the groups of agents that should be included for a given outcome.