Complex Mixtures Methods for In Vivo Toxicity Testing (1988) / Chapter Skim
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3. Testing Strategies and Methods
3. Testing Strategies and Methods
Pages 39-64
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From page 39... ...
Another factor, related to those two steps, that is of crucial importance in selecting the appropriate testing strategy is whether the mixture under study is a known entity of expected uniformity and formulation or an unknown mixture of varied origins, such as leachates and runoff. This chapter examines problem definition and choice of testing strategies from the perspectives of potential biologic effects of complex mixtures, the agents present in the mixtures, and the predictability of the data on one mixture with respect to other, related mixtures.
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From page 40... ...
If the questions asked are not defined properly, the testing strategy required cannot be developed, nor can one expect to obtain results that are applicable to potential adverse health effects in humans. The major difference between mixtures and single chemicals is not in the testing strategies chosen, but in the importance of problem definition before testing.
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From page 41... ...
Whatever end points are chosen must be considered in relation to human exposure to a given complex mixture and a set of plausible circumstances of exposure. QUESTIONS RELATED TO CAUSATIVE AGENTS Questions related to causative agents are peculiar to situations in which a toxic effect has been observed but the causative agents are unknown.
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From page 42... ...
Strategies for testing mixtures should avoid overcomplex programs and take into account the normal dose rate and frequencies of exposure. However, testing strategies must always be sensitive to unpredicted outcomes.
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From page 43... ...
In the case of some mixtures, identification of causative agents might not even be the information desired. The main interest might be to confirm or eliminate a causal relationship between an observed effect and an uncharactenzed matenal.
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From page 44... ...
A tier-testing approach has been applied to a number of complex mixtures (e.g., diesel emissions, synthetic fuels, and concentrated organic mixtures from drinking water) to identify potential toxic effects resulting from exposures to these mixtures.
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From page 45... ...
. Sample Matrix of Critical Variables FIGURE 3-2 Example of matrix testing in which critical variables for series of mixtures are manipulated to define aromaticity ~ ~ boundary conditions such that toxicologic testing of selected Miniature I 41; variables wou d result in pre ictability of effects within o, ~ _ 7~ 7t 9 ~ ~7 12 13 14 15 ~ ~ Ah 16 Selected Toxicologic Test(s)
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From page 46... ...
has been used in the field of genetic toxicity, in which the emphasis is on determining whether agents are genotoxic, whether metabolic conversion is a prerequisite for activity, and what sort of mechanisms might be involved (Heussneret al., 19851. Just as a diner might construct a meal by going through several courses on a complex menu, so an investigator can provide answers to the specific questions posed by selecting tests from an available battery.
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From page 47... ...
All soots from incomplete combustion are expected to contain carcinogenic polycyclic organic compounds, so the toxicologist might have to address the question of whether a new combustion source will produce soot that is more potent in a carcinogenicity bioassay than soot from current sources. A comparative-potency method for cancer risk assessment has been developed and tested with estimates of human lung-cancer risk (Albert et al., 19831.
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From page 48... ...
The testing included standard oral and dermal acute and subchronic toxicity tests, as well as a series of sensitization and irritation tests (Beck et al., 19821. Another example involved shale-derived fuels and other synfuels whose toxicity was determined primarily in a wide variety of comparative studies, including general toxicity, target-organ, behavioral, mutagenicity, carcinogenicity, teratogenicity, and neurotoxicity tests (see MacFarland et al., 1984, and Mehlman et al., 19841.
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From page 49... ...
Later, short-term mutagenicity and cellular-transformation bioassays were used to identify the most biologically active fractions and in some cases to identify specific chemicals in those fractions that could account for a portion of the mutagenic or tumorigenic activity (DeMarini, 19831. These studies concluded, for example, that polycyclic aromatic hydrocarbons in the neutral fraction contribute significantly to the tumor-initiating activity of the neutral fraction of CSC, whereas amines, aza-arenes, and other nitrogen-containing compounds account for much of the mutagenic activity of the basic fraction of CSC (DeMarini, 1983; IARC, 19861.
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From page 50... ...
Effort is concentrated on further fractionation and chemical characterization of biologically active fractions. then it at least appears that all the bioactivity is accounted for.
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From page 51... ...
, bioassay data on pure chemicals and analytic data on the bioactive components of a mixture are used. Data Base 1 Chemicals In a Mixture Toxic Chemicals in a Mixture \ Data Base 2 \ Chemical Toxicity Data FIGURE 3-6 Two data bases can be paired or combined; overlap represents toxic chemicals identified in mixture.
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From page 52... ...
LU FIGURE 3-7 Illustration of chem~cal-search and effect-search methods for determining causative agents in refixture. This method has been used with nitroparaffins (Hite and Skeggs, 1979)
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From page 53... ...
The prediction of acute toxic hazard, which includes many other components in addition to toxicity, has used a computer model that integrates many of the necessary pieces of the puzzle. The strategy to determine the toxicity factors needed for input into the hazard assessment has been to determine the individual and combined toxicities of a small select number of fire gases, predict the toxicity of the thermal decomposition products from materials based on the chemical analysis of the selected gases, and verify the prediction with a few animal exposures (Levin et al., in press)
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From page 54... ...
If the curve does not shift laterally (effective dose is unchanged) but the slope ofthe curve increases, the response to the toxicant is exaggerated by the potentiating agent.
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From page 55... ...
If the dose-response curves for the two agents are parallel, equivalent fractions of the median effective doses or equipotent doses of the agents can be selected. However, if the curves are not parallel, one must use equipotent doses; equivalent fractions of the median effective doses can result in misinterpretation of the action of the combination (Clausing and Bieleke, 1980; Mitchell, 19661.
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From page 56... ...
. It is not necessary to know the chemical composition of the mixture or the causative agents, but knowledge of the concentration of one or more chemical constituents could be useful.
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From page 57... ...
If We latter approach is selected, efficient expenmental designs can be extracted from the statistical literature on what are called fractional factorial designs. These are discussed in Chapter 5.
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From page 58... ...
The questions usually arise sequentially, so questions about the effects of a mixture would logically be raised before questions on causative agents. Questions on predictive value, however, have been raised when both a mixture's effects and agents were known and when very little was known about it other than what some of its constituents were.
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From page 59... ...
As new concerns are raised over exposures to mixtures, the factors discussed above should be considered in selecting strategies to provide data useful in answering questions about potential human risk and in selecting steps to protect public health. Figure 3-10 diagrams a hypothetical flow of a process that would consider each of the above factors and use the strategies presented here to address specific problems and questions.
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From page 60... ...
1983. Comparative potency method for cancer risk assessment application to diesel particulate emissions.
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From page 61... ...
III. Animal and human response to vapors of Stoddard Solvent.
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From page 62... ...
1986. Screening complex hazardous wastes for mutagenic activity using a modified version of the thin-layer chromatography Salmonella assay.
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From page 63... ...
1983. A comparative potency method for cancer risk assessment: Clarification of the rationale, theoretical basis, and application to diesel particulate emissions.
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From page 64... ...
1984. Ames assay chromatograms and the identification of mutagens in diesel particle extracts.
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