Science and Judgment in Risk Assessment (1994) / Chapter Skim
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4 Assessment of Toxicity
4 Assessment of Toxicity
Pages 56-67
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From page 56... ...
Data used in hazard identification typically are derived from animal studies and other types of experimental work, but can also come from epidemiologic studies. Dose-response evaluation is a more complex examination of the conditions under which the toxic properties of a chemical might be evidenced in exposed people, with particular emphasis on the quantitative relationship between dose and toxic response.
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From page 57... ...
Hazard Identification The first of the two questions typically considered in the assessment of chemical toxicity concerns the types of toxic effects that the chemical can cause. Can it damage the liver, the kidney, the lung, or the reproductive system?
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From page 58... ...
and extent of toxic response can be established. · The animals and animal tissues can be thoroughly examined by toxicologists and pathologists, so the full range of toxic effects produced by a chemical can be identified.
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From page 59... ...
As in the case of epidemiologic data, LARC expert panels rank evidence of carcinogenicity from animal studies. It is generally recognized by experts that evidence of carcinogenicity is most convincing when a chemical produces excess malignancies in several species and strains of laboratory animals and in both sexes.
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From page 60... ...
Limited evidence from animal studies and no human data Inadequate human and animal data or no data E Evidence of noncarcinogenicity No evidence of carcinogenicity from adequate human in humans and animal studies SOURCE: Adapted from EPA, 1987a. by the chemical under review, the strength of the supporting evidence, and the scientific merits of the data and their value for predicting human toxicity.
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From page 61... ...
Sufficient Experimental Animal Evidence or Limited Human Data: This category includes data from experimental-animal studies or limited human data that provide convincing evidence for the scientific community to judge whether the potential for developmental toxicity exists. The minimal evidence necessary to judge that a potential hazard exists generally would be data demonstrating an adverse developmental effect in a single appropriate, well-conducted study in a single experimental-animal species.
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From page 62... ...
To establish limits for human exposure, the experimental NOAEL is divided by one or more uncertainty factors, which are intended to account for the uncertainty associated with interspecies and intraspecies extrapolation and other factors. Depending on how close the experimental threshold is thought to be to the exposure of a human population, perhaps modified by the particular conditions of exposure, a larger or smaller uncertainty factor might be required to ensure adequate protection.
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From page 63... ...
The EPA (1987a) guidelines for health-risk assessment for suspected developmental toxicants states that, "owing primarily to a lack of understanding of the biological mechanisms underlying developmental toxicity, intra/interspecies differences in the types of developmental events, the influence of maternal effects on the doseresponse curve, and whether or not a threshold exists below which no effect will be produced by an agent," many developmental toxicologists assume a threshold for most developmental effects, because "the embryo is known to have some capacity for repair of the damage or insult" and "most developmental deviations are probably multifactorial." EPA (1988a,b)
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From page 64... ...
The Agency is currently supporting several major efforts to develop biologically based dose-response models for developmental toxicity risk assessment that include the consideration of threshold.
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From page 65... ...
In the absence of strong evidence to the contrary, it is generally assumed that such a potency factor estimated from animal data can be applied to humans to estimate an upper bound on the human cancer risk associated with lifetime exposure to a specified dosage. The dose-response step involves considerable uncertainty, because the shape of the dose-response curve at low doses is not derived from empirical observation, but must be inferred from theories that predict the shape of the curve at the low doses anticipated for human exposure.
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From page 66... ...
A second major trend in risk assessment stems from investigations indicating that some chemicals that increase tumor incidence might do so only indirectly, either by causing first cell-killing and then compensatory cell proliferation or by increasing rates of cell proliferation through mitogenesis. In either case,
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From page 67... ...
ASSESSMENT OF TOXICITY 67 increasing cell proliferation rates puts cells at increased risk of carcinogenesis from spontaneous mutation. Until a dose of such a carcinogen sufficient to cause the necessary toxicity or intracellular response is reached, no significant risk of cancer can exist.
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