Phthalates and Cumulative Risk Assessment The Tasks Ahead (2008) / Chapter Skim
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5 Cumulative Risk Assessment of Phthalates and Related Chemicals
5 Cumulative Risk Assessment of Phthalates and Related Chemicals
Pages 106-137
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From page 106... ...
This chapter assesses the empirical evidence of combined effects of several phthalates, of nonphthalate antiandrogens, and of phthalates and these other antiandrogens. Because of the importance of developmental effects, the overview focuses almost exclusively on experimental evidence from reproductivetoxicity studies.
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From page 107... ...
That question becomes all the more important when the two concepts produce different predictions of mixture effects. However, in only a few cases have dose addition and independent action been evaluated together against the same set of experimental mixture data with the aim of establishing whether either approach produces valid predictions of combined effects (for a review, see Kortenkamp et al.
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From page 108... ...
By activating differing effector chains, the argument goes, every component of a mixture of dissimilarly acting chemicals provokes effects independently of all other agents that are present, and this feature appears to lend itself to statistical concepts of independent events. Independent action is often held to be the default assessment concept when the similarity criteria of dose addition appear to be violated (COT 2002)
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From page 109... ...
Now consider mixture effects under the principle of dose addition. Accordingly, 5 dose units of A and 2.5 of B are expected
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From page 110... ...
for making choices between dose addition and independent action for phthalate mixtures leaves ambiguities that cannot readily be resolved without further empirical evidence, which would overrule any such heuristic arguments in any case. The committee concludes that the criteria applied by EPA are too narrow and restrictive because they leave out other chemicals that can disrupt male sexual differentiation but in ways that differ in some respects from phthalates (see Chapter 3)
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From page 111... ...
A secondary aim is to assess whether experimentally observed mixture effects agree quantitatively with the additivity expectations derived from dose addition. In dealing with those issues, it is important to recognize that dose addition and independent action often yield identical, experimentally indistinguishable, or trivially distinct predictions of additive combined effects.
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From page 112... ...
Their male offspring were examined for a wide array of effects typical of disruption of male sexual differentiation, including changes in fetal testosterone production, changes in anogenital distance, epididymal agenesis, retained nipples, gubernacular agenesis, hypospadias, and number of animals with malformations. Dose addition generally predicted larger effects than independent action, although for some end points the two concepts predicted equal effects.
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From page 113... ...
Model Dose addition Independent action Data mean and 90% confidence interval FIGURE 5-1 The committee's reanalysis of the combined effects of five phthalates on suppression of testosterone production (Howdeshell et al.
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From page 114... ...
Despite some uncertainty inevitably introduced by that assumption, dose addition gave predictions of combined effects of the mixed-mode antiandrogens that agreed better with the observed responses than did the expectations derived from independent action. For a number of end points -- including seminal vesicle weights, epididymal agenesis, and NR -- there was reasonable agreement with dose addition.
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From page 115... ...
COMBINED EFFECTS OF LOW DOSES OF PHTHALATES AND OTHER ANTIANDROGENS When it comes to judging the risks associated with low-level exposures, there are marked differences between the chemical-by-chemical approach to risk assessment and evaluations that take mixture effects into account. Where singlechemical risk assessments might yield the verdict "absence of risk," dose addition or independent action might yield the opposite conclusion.
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From page 116... ...
In vivo, effects on androgen-regulated Male Wistar rats exposed in utero Vinclozolin, flutamide, = DA Metzdorff et al. 2007 gene expression in prostate and postnatally procymidone In vivo, changes in reproductive organ Male Wistar rats exposed in utero Vinclozolin, flutamide, = DA Metzdorff et al.
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From page 117... ...
2008 exposed in utero procymidone, linuron, BBP, DBP, DEHP Note: AR, androgen receptor; CHO, Chinese hamster ovary, DA, dose addition; EDx, effective dose at x response level; FSH, follicle-stimulating hormone, IA, independent action; LH, luteinizing hormone; NR, nipple retention. a EDx observed / EDx predicted ≈ 1/0.9.
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From page 118... ...
produces a significant combined effect, consistent with expectations based on dose addition. the expected combined effect will be 9.5%.
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From page 119... ...
That gap can be bridged by reanalyzing published papers, but the task requires considerations of methodologic issues related to the concept and design of low-dose-mixture studies. Mixture Studies with Doses around Points of Departure for Risk Assessment: Methodologic Considerations A requirement for experimental studies intended to address the issue of mixture effects at doses around PODs for regulatory risk assessment is that such estimates are derived for each mixture component by using the same assay system (and end point)
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From page 120... ...
When all three chemicals were combined at doses equivalent to their own NOAELs, reductions in AGD of 50% were observed. Quantitatively, the effects agreed well with the responses predicted by dose addition (see Figure 5-3)
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From page 121... ...
. The predicted mixture effects were derived from doseresponse regression models for individual chemicals by using dose addition.
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From page 122... ...
. The expected mean combined effects derived from dose addition (DA, white bar)
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From page 123... ...
The potential for non-dose-additive combined effects to occur should be systematically explored. The work should not only focus on combinations of phthalates and other antiandrogens but consider the possibility that chemicals devoid of antiandrogenic activity -- for example, chemicals associated with testicular toxicity, such as cadmium -- may exacerbate mixture effects.
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From page 124... ...
Instead, a physiologically based approach for establishing grouping criteria for phthalates and other antiandrogens is strongly recommended. The recognition that androgen action is the driver of male sexual differentiation during development, with a multitude of underlying molecular mechanisms, implies that phenomenologic criteria should be used for grouping purposes.
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From page 125... ...
Independent action often yielded similar quantitative predictions but in some cases has led to substantial underestimation of combined effects. The committee could identify no case in which independent action predicted combined effects that were in agreement with experimentally observed responses and at the same time were larger than the effects anticipated by using dose addition.
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From page 126... ...
of chemicals 1-5 be 90, 3.5, 11.8, 17.8, and 3.95 mg/kg-d, respectively. By using dose addition, it is possible to predict the effects of a mixture of all five chemicals when the mixture ratios are in proportion to the individual BMDLs (black solid curve in Figure 5-5)
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From page 127... ...
. Joint effect of sum Sum of five single Combined effects curve of five single BMDLs BMDLs divided for mixture ratio in doses by five proportion to BMDLs 120 100 Effect (% of untreated controls)
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From page 128... ...
They can be the basis of reference values for cumulative effects, which can be used for risk assessment or standard-setting. Reference values for individual chemicals are estimated in relation to specific effect outcomes and toxic end points.
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From page 129... ...
Thus, NR in rats could be chosen as a common end point, and the BMDs or NOAELs for single chemicals could form the basis of cumulative risk assessments of phthalates and other antiandrogens. However, phthalates induce reductions in testosterone synthesis at lower doses than required for changes in NR.
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From page 130... ...
could be chosen for the estimation of reference values, which in turn are used to derive cumulative effects as a sum of toxic units or hazard indexes. However, this approach violates one of the preconditions of dose addition -- the induction of the same effect.
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From page 131... ...
Reference values for single chemicals A Tolerable cumulative exposure Exposure (human) Tolerable exposures for single chemicals Uncertainty factors Dose (animal)
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From page 132... ...
The authors developed a global quantitative structure-activity-relationship model that predicted that 8% of the chemicals would be active AR antagonists. Those efforts suggest that a large number of chemicals might be active in vivo AR antagonists capable of disrupting male sexual differentiation.
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From page 133... ...
Although a variety of molecular mechanisms are at play, dose addition provided equal or better approximations of mixture effects compared with independent action (when such comparisons
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From page 134... ...
The criteria recommended by EPA (2000) for guiding decisions between dose addition and independent action appear too narrow when applied to phthalates and other antiandrogens, particularly those requiring similarity in uptake, metabolism, distribution, and elimination and congruent dose-response curves for application of dose addition.
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From page 135... ...
1998. Effects on developmental landmarks and reproductive capability of 3, 3', 4,4'-tetrachlorobiphenyl and 3,3'4,4',5-pentachlorobiphenyl in offspring of rats exposed during pregnancy.
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From page 136... ...
2007. Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: Altered fetal steroid hormones and genes.
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From page 137... ...
2008. Screening of 397 chemicals and development of a quantitative structure-activity relationship model for androgen receptor antagonism.
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