Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity (2001) / Chapter Skim
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The Evaluative Process: Part II. Integration of Toxicity and Exposure Information
The Evaluative Process: Part II. Integration of Toxicity and Exposure Information
Pages 57-80
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From page 57... ...
INTERPRETATION OF TOXICITY DATA The interpretive section of the evaluative process considers all relevant information in the course of reaching a judgment about whether an exposure has the potential to cause developmental or reproductive toxicity in humans. In most cases, animal data are considered relevant indicators of human risk, unless there is modifying information that suggests otherwise.
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From page 58... ...
Animal data in which no adverse effects are observed do not always preclude human effects, nor do adverse effects in animals inevitably predict human toxicity. The evaluative process requires an integrated consideration of a variety of data.
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From page 59... ...
The conservative default assumption is that, without data to the contrary, treatment of an experimental animal by any route is assumed relevant to human exposure by any route. That default assumption can be dropped when adequate modifying information is available.
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In every case, default assumptions should be used sparingly and openly, with full disclosure of the degree of certainty. The general default assumptions proposed for use in this evaluative process are summarized below.
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From page 61... ...
For example, if a toxic effect occurs in animals through an inhibition of folic acid synthesis, that effect would not be considered relevant for humans because humans do not synthesize folic acid. It is unusual, however, to have such detailed knowledge about mechanisms of toxicity from experimental animal studies.
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From page 62... ...
Toxicity data are scaled directly from experimental animals to humans on the basis of minute volume per kilogram of body weight for inhaled materials and by weight (or volume) of the dose per body weight or surface area for other routes of exposure.
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From page 63... ...
Screening studies conducted in animals using repeated exposures throughout organogenesis may also be followed up with more discrete exposures to determine critical windows. For example, the finding that boric acid caused a number of skeletal alterations in studies in rats, mice, and rabbits with exposure throughout organogenesis (Heinde]
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From page 64... ...
Because data on human dose-response relationships are rarely available, the dose-response evaluation is usually based on an assessment of data from tests performed in experimental animals. Box 3-2 defines terms commonly used in quantitative evaluations.
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From page 65... ...
. The MOE expresses the magnitude of difference between a level of anticipated human exposure and the highest level at which there is no significant increase in the frequency of an adverse effect (NOAEL)
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From page 66... ...
, or by conducting pairwise tests that appropriately control the overall Type ~ error, such as Dunnett's test for independent, continuous data (Dunnett 1955, 1964~. It should be recognized that the power of reproductive and developmental toxicity studies to detect effects with typicaDy 20 animals per dose group varies for endpoints within and between studies.
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From page 67... ...
Figure 3-2 illustrates the relationship between the dose-re1The convention of using BMDL as the lower confidence limit follows the terminology proposed in the paper by Crump (1995) ; this has also been adopted for use in the EPA BMDS software, since it refers explicitly to the lower confidence limit value.
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From page 68... ...
In each case, the NOAEL is 10 ma/ kg/ d and the LOAEL is 100 mg/kg/ d, assuming Mat the increase above control at these exposures is significant. spouse model, the BMD and the BMDL for a BMR of 10% above background for a dichotomous endpoints Using the BMD approach, one can calculate a value for each effect of an agent for which sufficient data are available.
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From page 69... ...
the degree of change considered adverse for that effect is used as the BMR and the data are modeled as continuous data; (2) if individual data are available and there is an accepted level of change considered adverse, the data can tee "dichotomized" (number above or below the cutoff value, perhaps based on some quartile of the distribution)
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From page 70... ...
The Subcommittee on Reproductive and Developmental Toxicology recommends that exposure duration should be considered in developmental and reproductive toxicity assessments alike. The reason for this recommendation is that adjusting for duration of exposure is likely to be more conservative with repeated exposures than with single exposures, even for developmental toxicity data (Weller et al.
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From page 71... ...
Pharmacokinetic data may be used to adjust exposure concentrations for such agents. As more pharmacokinetic information becomes available, it is important to me ze the dependence on default assumptions and to encourage the use of pharmacokinetic data to determine the appropriate dosimeters to use in adjusting exposure levels and determining internal dose.
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From page 72... ...
The evaluative process uses the UET~ both to avoid the connotation that it is the RfD or reference concentration (RfC) value derived by EPA or the ADI derived for food additives by the Food and Drug Administration, both of which consider all types of noncancer toxicity data.
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From page 73... ...
In some cases, a small MOE can be considered protective of health. For example, the lithium assessment conducted using a similar evaluative process MA.
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The NOAEL approach does not allow for considerations of variability in the data, but use of the lower confidence limit on dose in the BMD approach does account for vari
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From page 75... ...
Consideration of the reliability of the reproductive and developmental data set and of non-reproductive toxicity data can be an important part of the evaluative process. The inclusion of all available information in the evaluation and the use of scientific judgment are recommended as most likely to lead to the most informed estimate of the risk of anticipated human exposure.
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From page 76... ...
dosing regimen is used to meet regulatory requirements, a central premise in developmental toxicology is that adverse developmental outcomes can result from a single pre- or postnatal exposure. An experimental animal study that uses once-daily gavage might not produce the same exposure profile as human dietary exposure to an agricultural chemical, for example.
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From page 77... ...
Therefore, a singleexposure study would underestimate the toxicity of repeated exposures. Determining whether a particular developmental outcome results from a single acute exposure or from repeated exposures requires additional studies that are not often available.
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From page 78... ...
In another chemical evaluation, data might be judged sufficient to determine human risk potential, but in the judgment of the evaluators there might be large degrees of uncertainty because of reliance on default assumptions or because of the inherent uncertainty in some of the data that are central to the evaluation. In each instance, evaluators will cite specific data needs if they determine that the data will materially improve the certainty of an existing judgment about human risk.
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From page 79... ...
Moreover, a lack of detailed exposure information will be common in this type of evaluative process but is necessary for a risk characterization. In this case, the summary communicates to Navy environmental health practitioners scientific judgment on chemical risk for reproductive and developmental toxicity.
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From page 80... ...
For example, although there might be great certainty that the data qualitatively predict human health risk potential, the nature and degree of exposure might be poorly understood. In that case, the evaluative summary will clearly state that there is reasonable certainty of human risk potential and explain why the quantitative uncertainty (missing, inadequate exposure data)
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