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David W Gaylor

Publications and source records attributed to David W Gaylor.

5 recordsLinked to original sources
PubMed2003

Comparison of cancer risk estimates based on a variety of risk assessment methodologies.

The EPA guidelines recommend a benchmark dose as a point of departure (PoD) for low-dose cancer risk assessment. Generally the PoD is the lower 95% confidence limit on the dose estimated to produce an extra lifetime cancer risk of 10% (LTD(10)). Due to the relatively narrow range of doses in two-year bioassays and the limited range of statistically significant tumor incidence rates, the estimate of the LTD(10) is constrained to a relatively narrow range of values. Because of this constraint, simple, quick estimates of the LTD(10) can be readily obtained for hundreds of rodent carcinogens from the Carcinogenic Potency Database (CPDB) of Gold et al. Three estimation procedures for LTD(10) are described, using increasing information from the CPDB: (A) based on only the maximum tolerated dose (the highest dose tested); (B) based on the TD(50); and (C) based on the TD(50) and its lower 99% confidence limit. As expected, results indicate overall similarity of the LTD(10) estimates and the value of using additional information. For Method (C) the estimator based on the [[(TD(50))(0.36) x (LoConf)(0.64)]/6.6] is generally similar to the estimator based on the one-hit model or multistage model LTD(10). This simple estimate of the LTD(10) is applicable for both linear and curved dose responses with high or low background tumor rates, and whether the confidence limits on the TD(50) are wide or tight. The EPA guidelines provide for a margin of exposure approach if data are sufficient to support a nonlinear dose-response. The reference dose for cancer for a nonlinear dose-response curve based on a 10,000-fold uncertainty (safety) factor from the LTD(10), i.e., the LTD(10)/10,000, is mathematically equivalent to the value for a linear extrapolation from the LTD(10) to the dose corresponding to a cancer risk of <10(-5) (LTD(10)/10,000). The cancer risk at <10(-5) obtained by using the q(1)(*) from the multistage model, is similar to LTD(10)/10,000. For a nonlinear case, an uncertainty factor of less than 10,000 is likely to be used, which would result in a higher (less stringent) acceptable exposure level.

Animals↗
PubMed2002

Statistical calculation of detection limits for DNA adducts using the 32P-postlabeling assay with a standard addition procedure.

The 32P-postlabeling assay is widely used for the analysis of DNA adducts. Some adducts can be detected with very high sensitivity but quantification can be unreliable, particularly if it is based only on comparison with unmodified nucleotides (relative adduct labeling, RAL values). Furthermore, guidelines to calculate detection limits for adduct concentrations are lacking. This is particularly important for human biomonitoring studies of environmental exposures, where a low adduct level can remain undetected. Reports of null results of toxicity studies should always include a limit of detection, indicating the effect magnitude that would have produced, with a given probability of false negative (type II error), a statistically significant increase (type I error). Here, we report on a procedure based on t-statistics to calculate two types of detection limits, the "critical level (CL)" and the "detection level (DL)". The first is the size of the difference between exposed and controls required to achieve statistical significance. The second is the size of the difference that will be detected with a chosen probability of a false negative. For the degrees of freedom (d.f.) to be used for the t-values, a general formula is given so that different standard deviations and group sizes of control and exposed groups can be handled. A sample calculation of the whole procedure is shown, using the null data for the formation of a particular adduct in lung DNA of styrene-treated mice, analyzed by 32P-postlabeling. The procedure takes into account: (i) TLC-specific background radioactivity; (ii) variability within the control and exposed groups; and (iii) confidence limits for the factor to convert 32P-radioactivity to amounts of adduct. The latter step incorporates the variance of the differences between the samples and replicates spiked with adduct standard. A statement such as follows is the result: the concentration of the alpha-isomer adduct of styrene 7,8-oxide at the O(6)-position of guanine in mouse lung DNA would have to be at least 12 adducts per 10(8) nucleotides to be detected in the given experiment on a 5% level (type I error), with a probability of 5% to miss an existing effect (type II error).

Animals↗
PubMed2002

A procedure for developing risk-based reference doses.

Reference doses (RfDs) for toxic substances based on a no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL) are established to restrict human exposures to only nontoxic or minimally toxic levels. In order to calculate a risk-based RfD, for the point of departure it is necessary to replace a NOAEL or LOAEL by a benchmark dose (BMD) estimated to be associated with a specified level of estimable risk in or near the low end of an experimental dose range. Then the RfD is calculated by dividing the BMD by a series of uncertainty factors. Among these uncertainty factors is one for interindividual sensitivity, typically assigned a value of 10. If information is available on interindividual sensitivity, this default factor can be replaced with a factor expected to provide protection for a specified proportion of a population. Examination of published databases suggests interindividual effects often to be approximately log-normal. For example, in order to illustrate the procedure for establishing a risk-based RfD, a standard deviation of the logarithm (base e) of individual sensitivity of 1.7 was selected, i.e., a factor of 5.5. This value is near the upper range of values reported in the literature (D. Hattis et al., 1999, in "Characterizing Human Variability in the Risk Assessment Process," ILSI Press, Washington, DC). Using this information in combination with an RfD based on a benchmark dose associated with a specified level of risk, the risk at the RfD can be estimated. For example, a benchmark dose associated with a risk of 10% divided by 60, to account for interindividual variation, is expected to limit risk at the RfD to about 1 in 10,000. If the standard deviation of the logarithm (base e) of individual sensitivity is 1.2, a more typical value, the divisor is approximately 20. These would replace an RfD having an unknown risk based on the LOAEL divided by 100. Or, an RfD with a specified level of risk could be estimated. The estimate of risk can be improved for a specific case by replacing an overall estimate of the standard deviation for interindividual variability by an estimate of the standard deviation for a particular class of chemicals and/or biological endpoint, if available. Risks can be substantially lower for smaller values of interindividual variability. Determination of an RfD still would require an additional uncertainty factor for animal to human extrapolation.

Adult↗