Environmental Neurotoxicology (1992) / Chapter Skim
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6. Risk Assessment
6. Risk Assessment
Pages 111-122
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From page 111... ...
discussed the development of those methods. Compared with the work on risk assessment of neurotoxicants, the development of methods for quantitative risk assessment of carcinogens has been built on a larger body of mechanistic information and hypotheses that permits quantitative description of the cellular and molecular events involved in chemical- and radiation-induced carcinogenesis.
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From page 112... ...
, and the expected ranges and distribution of doses from individual to individual—are incorporated into a risk characterization. In the case of dichotomous events, such as the presence or absence of a diagnosable malignancy or death, the process results in a probability estimate that can be expressed as an increase in individual risk or, with appropriate adjustments, as an estimate of increased population risk.
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From page 113... ...
, an examination of the effects of such a decrease on an overall population distribution of IQ scores (Figure 6-1) reveals the potential for very important consequences of low-level lead exposure for society as a whole.
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From page 114... ...
Although, in appropriate cases, statistical analysis can be important in validating models based on hypothesized mechanisms of action, the available data are usually insufficient to resolve critical issues, such as the predicted response at exposures below those on which the data were collected. An essential part of developing risk-assessment methods is therefore the integration of biologically based models that incorporate our understanding of mechanism of action.
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From page 115... ...
, whereas senescence includes a progressive loss of specific neurons and an apparently selective loss of function. Because the CNS develops from a limited set of cells early in development, it is appropriate to assume that exposure to neurotox~cants during critical periods of brain development can be without a threshold; data on x-irradiationinduced brain injury support this assumption (Schull et al., 1990~.
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From page 116... ...
After producing ma~nmallikelihood estimates of the mean and standard deviation of the threshold distribution, the distribution of blood lead concentrations was estimated. Wyzga thereby determined that the probability that a randomly chosen male from the general population would exceed the threshold and exhibit extensor muscle weakness would be 0.01.
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From page 117... ...
Assuming that to be its fundamental mechanism of action, one can develop a mathematical model based on the biology of receptor-ligand interactions. Receptor-ligand binding is well described by classical mathematical models derived from LineweaverBurk equations of enzyme kinetics (Silbergeld, 1990~.
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From page 118... ...
Nep}~ila orb web spider toxins Argiope orb web spider towns ~y-Philanthotoxin MK 801 Ketamine GABAA receptor or channel Bicuculline N-Methyl-D-aspartate Lindane 1-Glutamate Dieldrin Kainate Picrotoxinin Quisqualate CABAL receptor or channel Phaclofen Muscimol Avermectin B'a Barbituates Benzodiazepines Ethanol Gl~rcine receptor or channel Strychnine Baclofen Pre~ynaptic tunnel ,6-Bungaroto~nn cY-Latrotonn Botulinum toxin Tetanus toxin Taipomn linear no-threshold model might be appropriate to estimate the effects of cytotoxic agents encountered during critical periods of development. Radiation is the classic example of such an exposure.
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From page 119... ...
Design and reporting of both animal and epidemiologic experiments could be modified in several respects to facilitate modeling of neurotoxic end points for risk assessment (Wyzga, 1990~. It would be useful to conduct studies at a number of carefully measured exposure concentrations, including ones of environmental relevance.
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From page 120... ...
Mechanistic understanding is the most powerful tool in developing models for quantitative risk assessment, for evaluating predictions of dose-response relationship outside the measurable range, and for extrapolating across species reliably. Modelbuilding in science is important in identifying critical data gaps.
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From page 121... ...
Efforts should be directed to developing a broader range of biologically based models for risk assessment of neurotoxicants, with emphasis on nondichotomous events. It might be useful to examine the research on model-building that is already under way in neuroscience, particularly cognitive science.
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