Modeling for Risk Assessment of Neurotoxic Effects

The regulation of noncancer toxicants, including neurotoxicants, has usually been based upon a reference dose (allowable daily intake). A reference dose is obtained by dividing a no-observed-effect level by uncertainty (safety) factors to account for intraspecies and interspecies sensitivities to a chemical. It is assumed that the risk at the reference dose is negligible, but no attempt generally is made to estimate the risk at the reference dose. A procedure is outlined that provides estimates of risk as a function of dose. The first step is to establish a mathematical relationship between a biological effect and the dose of a chemical. Knowledge of biological mechanisms and/or pharmacokinetics can assist in the choice of plausible mathematical models. The mathematical model provides estimates of average responses as a function of dose. Secondly, estimates of risk require selection of a distribution of individual responses about the average response given by the mathematical model. In the case of a normal or lognormal distribution, only an estimate of the standard deviation is needed. The third step is to define an adverse level for a response so that the probability (risk) of exceeding that level can be estimated as a function of dose. Because a firm response level often cannot be established at which adverse biological effects occur, it may be necessary to at least establish an abnormal response level that only a small proportion of individuals would exceed in an unexposed group. That is, if a normal range of responses can be established, then the probability (risk) of abnormal responses can be estimated. In order to illustrate this process, measures of the neurotransmitter serotonin and its metabolite 5-hydroxyindoleacetic acid in specific areas of the brain of rats and monkeys are analyzed after exposure to the neurotoxicant methylene-dioxymethamphetamine. These risk estimates are compared with risk estimates from the quantal approach in which animals are classified as either abnormal or not depending upon abnormal serotonin levels.     

Perspectives on Incorporating Human Neurobehavioral End Points in Risk Assessments

Three topics are addressed: (1) measurement issues (e.g., the reliability and validity of neurobehavioral test scores), (2) general principles of assessment, including test selection, and (3) interpretation of scores. Psychological tests generally perform as well as medical tests in terms of reliability and validity. Test manuals, assessment textbooks, and psychologists are useful resources to the risk assessor. The variety of different tests employed in neurobehavioral studies complicates interstudy comparisons. In addition, tests that ostensibly assess the same general domain of function might assess somewhat different abilities within that domain. Although a uniform battery for use in all studies seems desirable, the battery appropriate for a specific study depends on study goals, knowledge about the mechanism(s) of neurotoxicity, nature of the study population, and pattern of exposure. Exposure-related neurobehavioral deficits are generally indicators of "altered function" rather than of "clinical disease." Limiting concern to end points corresponding to clinical disease might not be appropriate. Many neurobehavioral diagnoses are phenomenological and a neurotoxicant might cause a unique pattern of deficits for which no label has been created. The concern that a small shift in the central tendency of a distribution of test scores has no significance for the individual should be reexamined in light of the prevention paradox, formulated on the basis of epidemiologic studies of chronic disease. Poor performance on a neurobehavioral test does not necessarily map clearly onto underlying behavioral or neural substrate. The absence of such linkages, given current knowledge about brain-behavior relationships, should not reduce confidence in neurobehavioral end points. Use of neurobehavioral test scores involves considerations that differ little from those that the risk assessor routinely addresses in using end points commonly used in research on other topics in environmental epidemiology.     

Determination of a Tolerable Daily Intake of DDT for Consumers of DDT Contaminated Fish from the Lower Yakima River, Washington*

DDT, DDE, and DDD have been detected at elevated concentrations in sediments and fish of the Yakima River, its tributaries and drainages. An assessment was conducted to evaluate the public health significance of eating fish from the river. This was accomplished by establishing a daily intake level of DDT for the population of greatest concern, and comparing this level to a tolerable daily intake. The most sensitive and highly exposed group was determined to be breastfeeding infants. Infant daily intakes of DDT, based on estimated mother's DDT-breast milk levels, were compared to a recommended tolerable daily intake. Results indicate that mothers who frequently consume Yakima River bottom-feeding fish could have breast milk DDT concentrations sufficiently high to expose their infants to levels above the tolerable daily intake.     

Challenges Confronting Risk Analysis of Potential Thyroid Toxicants

Screening and testing for potential thyroid toxicants using endpoints of thyroid function, including circulating levels of thyroid hormones and thyrotropin, will not capture toxicants that directly interfere with thyroid hormone action at the receptor. The goals of the present review are to provide a critique of the literature focused on thyroid hormone and brain development as it relates to testing and evaluating thyroid toxicants, and to propose possible solutions to this perceived dilemma.     

A Randomization Test-Based Method for Risk Assessment in Neurotoxicology

A current trend in risk assessment for systemic toxicity (noncancer) endpoints is to utilize the observable range of the dose-effect curve in order to estimate the likelihood of obtaining effects at lower concentrations. Methods to accomplish this endeavor are typically based on variability in either the effects of fixed doses (benchmark approaches), or on variability in the doses producing a fixed effect (probabilistic or tolerance-distribution approaches). The latter method may be particularly desirable because it can be used to determine variability in the effect of an agent in a population, which is an important goal of risk assessment. This method of analysis, however, has typically been accomplished using dose-effect data from individual subjects, which can be impractical in toxicology. A new method is therefore presented that can use traditional groups-design data to generate a set of dose-effect functions. Population tolerances for a specific effect can then be estimated from these model dose-effect functions. It is based on the randomization test, which assesses the generality of a data set by comparing it to a data set constructed from randomized combinations of single point estimates. The present article describes an iterative line-fitting program that generates such a data set and then uses it to provide risk assessments for two pesticides, triadimefon and carbaryl. The effects of these pesticides were studied on the locomotor activity of laboratory rats, a common neurobehavioral end point. Triadimefon produced dose-dependent increases in activity, while carbaryl produced dose-dependent decreases in activity. Risk figures derived from the empirical distribution of individual dose-effect functions were compared to those from the iterative line-fitting program. The results indicate that the method generates comparable risk figures, although potential limitations are also described.     

Benchmark Dose Calculations for Methylmercury-Associated Delays on Evoked Potential Latencies in Two Cohorts of Children

Delays in evoked potential latencies were observed at increased exposures to methylmercury from seafood in two cohorts of children. Because this outcome parameter appeared to be virtually independent of confounders, including cultural differences, a joint analysis of benchmark doses was carried out. Comparable cohort members included 382 Faroese and 113 Madeiran children without middle ear infection or neurological disease at age seven years. Maternal hair-mercury concentrations at parturition in the Faroese cohort ranged from 0.6 to 39.1 microg/g (geometric average, 4.49 microg/g). In Madeira, mothers who had not changed their diet since pregnancy had current hair-mercury concentrations ranging from 1.1 to 54.4 microg/g (geometric average 10.14 microg/g). The mercury-associated delay in peak III latencies at two frequencies (20 and 40 Hz) showed similar regression equations in the two groups of children, and benchmark dose calculations were therefore carried out for the two groups separately and jointly. For a doubling of a 5% prevalence of abnormal results of the peak III latencies at 40 Hz in a linear dose-response model, the benchmark dose for the maternal hair-mercury concentration was 8.79 microg/g for the Faroese children; 8.04 microg/g for the Madeiran children; and 9.46 microg/g for both groups. Results were similar for the 20 Hz condition. Benchmark dose results were substantially lower using a logarithmic or square root curve function, although the difference in fit between the curves was far from statistically significant. The benchmark results using evoked potential latencies are in close agreement with results based on neuropsychological test performance.     

Quantitative Risk Assessment for Developmental Neurotoxic Effects

Developmental neurotoxicity concerns the adverse health effects of exogenous agents acting on neurodevelopment. Because human brain development is a delicate process involving many cellular events, the developing fetus is rather susceptible to compounds that can alter the structure and function of the brain. Today, there is clear evidence that early exposure to many neurotoxicants can severely damage the developing nervous system. Although in recent years, there has been much attention given to model development and risk assessment procedures for developmental toxicants, the area of developmental neurotoxicity has been largely ignored. Here, we consider the problem of risk estimation for developmental neurotoxicants from animal bioassay data. Since most responses from developmental neurotoxicity experiments are nonquantal in nature, an adverse health effect will be defined as a response that occurs with very small probability in unexposed animals. Using a two-stage hierarchical normal dose-response model, upper confidence limits on the excess risk due to a given level of added exposure are derived. Equivalently, the model is used to obtain lower confidence limits on dose for a small negligible level of risk. Our method is based on the asymptotic distribution of the likelihood ratio statistic (cf. Crump, 1995). An example is used to provide further illustration.     

Duration Adjustment of Acute Exposure Guideline Level Values for Trichloroethylene Using a Physiologically-Based Pharmacokinetic Model

Acute Exposure Guideline Level (AEGL) recommendations are developed for 10-minute, 30-minute, 1-hour, 4-hours, and 8-hours exposure durations and are designated for three levels of severity: AEGL-1 represents concentrations above which acute exposures may cause noticeable discomfort including irritation; AEGL-2 represents concentrations above which acute exposure may cause irreversible health effects or impaired ability to escape; and AEGL-3 represents concentrations above which exposure may cause life-threatening health effects or death. The default procedure for setting AEGL values across durations when applicable data are unavailable involves estimation based on Haber's rule, which has an underlying assumption that cumulative exposure is the determinant of toxicity. For acute exposure to trichloroethylene (TCE), however, experimental data indicate that momentary tissue concentration, and not the cumulative amount of exposure, is important. We employed an alternative approach to duration adjustments in which a physiologically-based pharmacokinetic (PBPK) model was used to predict the arterial blood concentrations [TCE(a)] associated with adverse outcomes appropriate for AEGL-1, -2, or -3-level effects. The PBPK model was then used to estimate the atmospheric concentration that produces equivalent [TCE(a)] at each of the AEGL-specific exposure durations. This approach yielded [TCE(a)] values of 4.89 mg/l for AEGL-1, 18.7 mg/l for AEGL-2, and 310 mg/l for AEGL-3. Duration adjustments based on equivalent target tissue doses should provide similar degrees of toxicity protection at different exposure durations.     

Perspectives on Incorporating Human Neurobehavioral End Points in Risk Assessments

Three topics are addressed: (1) measurement issues (e.g., the reliability and validity of neurobehavioral test scores), (2) general principles of assessment, including test selection, and (3) interpretation of scores. Psychological tests generally perform as well as medical tests in terms of reliability and validity. Test manuals, assessment textbooks, and psychologists are useful resources to the risk assessor. The variety of different tests employed in neurobehavioral studies complicates interstudy comparisons. In addition, tests that ostensibly assess the same general domain of function might assess somewhat different abilities within that domain. Although a uniform battery for use in all studies seems desirable, the battery appropriate for a specific study depends on study goals, knowledge about the mechanism(s) of neurotoxicity, nature of the study population, and pattern of exposure. Exposure-related neurobehavioral deficits are generally indicators of "altered function" rather than of "clinical disease." Limiting concern to end points corresponding to clinical disease might not be appropriate. Many neurobehavioral diagnoses are phenomenological and a neurotoxicant might cause a unique pattern of deficits for which no label has been created. The concern that a small shift in the central tendency of a distribution of test scores has no significance for the individual should be reexamined in light of the prevention paradox, formulated on the basis of epidemiologic studies of chronic disease. Poor performance on a neurobehavioral test does not necessarily map clearly onto underlying behavioral or neural substrate. The absence of such linkages, given current knowledge about brain-behavior relationships, should not reduce confidence in neurobehavioral end points. Use of neurobehavioral test scores involves considerations that differ little from those that the risk assessor routinely addresses in using end points commonly used in research on other topics in environmental epidemiology.