Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) / Chapter Skim
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3 Current Practices for Assessing Risk for Developmental Defects and Their Limitations
3 Current Practices for Assessing Risk for Developmental Defects and Their Limitations
Pages 26-57
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From page 26... ...
THE DEVELOPMENTAL TOXICITY RISK ASSESSMENT PROCESS "Human health risk assessment" refers to the process of systematically characterizing potential adverse health effects in humans that result from exposure to chemicals and physical agents (NRC 1983~. For developmental toxicity, this assessment means evaluating the potential for chemical exposure to cause any of four types of adverse developmental end points: growth retardation; gross, skel26
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From page 27... ...
. -_~ec.:~~__~:~_~ ~ ~ 1/ ~ \ / Cell Signaling \Pathway Research `~ Gene-Environment \ Research Exposure assessment \/ ~ /\ /\ Development of \ Regulatory Options \ Public Health, \ Social, Ethical, Economic, Political / Implications l / FIGURE 3-1 Risk assessment and risk management paradigm from the NRC modified for developmental toxicity risk assessments.
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From page 28... ...
For glycol ethers, retinoic acid, valproic acid, and their derivatives and for several other commercial products and therapeutics, good SAR data exist for developmental effects. Recently, SARs were reported for valproic acid derivatives that activate the peroxisomal proliferation pathway and cause developmental toxicity (Lampen et al.
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From page 29... ...
There must be confidence that the test outcome will accurately classify most chemicals by their potential to cause human developmental toxicity. Furthermore, the required sensitivity and selectivity will vary, depending on the purpose of the test.
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From page 30... ...
Intrinsic Limitations Alternatives to in vivo testing will never detect all the developmental toxicants that have actions in pregnant mammals. This is true for several reasons.
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From page 31... ...
There is currently no consensus on how to categorize, stratify, or quantify the developmental toxicity of chemicals. Most validation studies have used a binary classification: developmental toxicants or nontoxicants (Parsons et al.
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From page 32... ...
An additional problem in categorizing chemicals, even those tested according to standard protocols, is that toxicokinetics and metabolism are rarely investigated sufficiently to indicate whether a negative outcome in viva is a reflection of a true lack of inherent developmental toxicity potential or a low embryonic exposure. This outcome can lead to a situation in which a chemical is correctly identified as a potential developmental toxicant from an in vitro test, but the effective exposure can never be achieved in viva.
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From page 33... ...
CURRENT PRACTICES FOR ASSESSING RISK FOR DEVELOPMENTAL DEFECTS 33 TABLE 3-1 Systems Proposed as Alternatives to Pregnant Mammals to Test for Developmental Toxicitya System End Point Monitored References Mammalian embryos ex utero Rodent whole-embryo culture Morphogenesis Webster et al. 1997 Rodent embryonic organ culture: limb; Morphogenesis Kochhar 1982; palate Abbott et al.
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From page 34... ...
Because there is uncertainty in extrapolation from animal studies to humans, several assumptions are made, including the following: (1) an agent that causes an adverse developmental effect in experimental animals might cause an effect in humans; (2)
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From page 35... ...
Additionally, the authors held to the premise that adverse developmental effects represented a continuum of responses or at least a number of interrelated effects including in utero growth retardation, death of the products of conception, frank malformations, and functional deficits that manifest themselves in later stages in life. Hence, an effect on any one of these end points in experimental animals or human studies was considered a basis for concordance.
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From page 36... ...
For industrial and environmental chemicals, the dosing regimens at or even above MTDs, as applied in hazard identification studies, typically contrast sharply with anticipated human exposures that are commonly much lower in extent or magnitude, often uncertain, or even entirely unknown. Because of the design of developmental hazard identification studies, the overwhelming majority of the more than 1,200 agents found to elicit adverse developmental outcomes in experimental animals were tested at doses many times higher than anticipated human exposures during pregnancy and have often elicited extreme maternal toxicity.
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From page 37... ...
Case series comprise an important first step in assessing relationships between exposures and adverse pregnancy outcomes. Many developmental toxicants are first recognized by astute clinicians who correlate specific patterns of developmental defects or developmental disabilities with specific exposures during pregnancy.
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From page 38... ...
1990) , and potent developmental toxicants, such as isotretinoin and thalidomide, are very strongly associated with major malforma
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1985~. Although conventional epidemiological studies have been useful in quantifying the magnitude of risk produced by those potent agents, they were first identified as human developmental toxicants through case reports.
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From page 40... ...
Uncertainty factors, which are derived from animal and human data, generally involve dividing by a default value of 10 to account for uncertainties (EPA 1991~. Uncertainty factors for developmental effects are applied to the NOAEL or BMD to include a 10-fold factor for interspecies extrapolation and a 10-fold factor for intraspecies variation.
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From page 41... ...
Chapters that follow will show how important new information on species differences and data on human variability can replace our reliance on such default approaches for developmental toxicity risk assessment. Exposure Assessment Exposure assessments are a critical component of the risk characterization process.
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From page 42... ...
For developmental toxicants, these key questions are related to the amount and form of the toxicant that reaches tissues of the conceptus. Such knowledge can reduce the uncertainty in the extrapolation of results collected from experimental animals for the prediction of hazard associated with exposure of pregnant women.
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From page 44... ...
Retinoids were already known to cause developmental toxicity in pregnant animals of every test species examined. The regulatory decision concerning retinoid creams for dermal application was based on barely detectable changes in the blood concentrations of endogenous retinoids after dermal application of the drug.
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From page 45... ...
For example, in one type of conventional developmental toxicology study design, studies initiate dosing at the beginning of organogenesis of the chosen test species. The study design might be flawed for compounds that have a long half-life, because steady-state concentrations are reached only after dosing for approximately four half-lives.
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From page 46... ...
The maternal AUC has often been used to draw conclusions about the chemical exposure of the conceptus without the availability of any toxicokinetic information from the conceptus compartments. The assessment of conceptus toxicant levels can be invaluable for understanding animal species differences in develop
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From page 47... ...
mental toxicity and for assessing the validity of negative in vivo studies for compounds otherwise suspected to have high potential for developmental toxicity. One chemical for which toxicokinetic data have been collected from maternal and conceptus compartments at two stages of pregnancy is 2-methoxyacetic acid, the proximate developmental toxicant derived from the maternal oxidation of 2-methoxyethanol, an ethylene glycol ether used as an industrial solvent.
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From page 48... ...
in the conceptus. The significance of considering both AUC and Cmax measurements for developmental toxicity risk assessment is especially important because of known temporal differences in tissue susceptibility.
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From page 49... ...
In summary, the correct application of toxicokinetic information in the determination of hazard and in judgments concerning risk characterization requires a broad view of pharmacological, toxicological, and embryological principles. These principles have guided the committee in their considerations on how most effectively to incorporate recent advances in molecular and developmental biology in risk assessment.
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From page 50... ...
. Maternal hair concentrations, as well as blood concentrations, of MeHg correlate with adverse developmental outcomes in the children exposed in utero (Clarkson 1987~.
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From page 51... ...
Thus, biomarkers of exposure have the potential to be critical in establishing potential risk at a sensitive period during development. For developmental toxicants that can produce developmental defects at dosages or concentrations not causing identifiable immediate adult toxicity (e.g., thalidomide and cigarette smoking)
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From page 52... ...
Critical applications for such biomarkers in developmental toxicology are in the identification of those at risk, with hopes of reducing that risk by modifying exposure and by developing other intervention strategies to decrease the incidence of developmental defects. Other biomarkers include indicators of normal cell processes (e.g., cell proliferation that may occur at inappropriate times or at different levels of expression)
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From page 53... ...
The category also includes polymorphisms for genes encoding components of developmental processes, although the latter are still not well understood. The acquired category includes previous disease conditions, antibody immunity, nutrition, other chemical and pharmaceutical exposures, and various capacities for homeostasis.
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From page 54... ...
Such assumptions are generically used because information on the mechanisms of action for specific developmental toxicants is inadequate and because the lack of mechanistic information results in the use of default uncertainty factors. The most important limitation is the paucity of human data, and the lack of methodology to adequately assess humans.
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From page 55... ...
The resolving power of animal studies to distinguish an increase in the rate of frank malformations is relatively weak. For example, in a study with 20 pregnant rats per dose group, an increase in the malformation rate must double from the background rate to be statistically significant.
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From page 56... ...
This lack of understanding again results in the application of additional child-specific uncertainty factors in efforts to address the sensitivity of the developing conceptus rather than emphasizing the search for the biological understanding of critical windows of susceptibility. A corollary to the problem of low-dose extrapolation is the assumption that effects observed at high-dose concentrations in experimental animals are relevant to the prediction of risk of adverse effects at ambient exposure concentrations.
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From page 57... ...
The information presented in this chapter, and in the next chapter on mechanisms of developmental toxicants (Chapter 4) , will be used to define the current state of developmental toxicology and will provide a context for how advances in developmental biology and genomics can improve the approaches for protecting public health.
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