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D Gaylor

Publications and source records attributed to D Gaylor.

10 recordsLinked to original sources
PubMed1999

No threshold dose for estradiol-induced sex reversal of turtle embryos: how little is too much?

Risk assessments for nongenotoxic chemicals assume a threshold below which no adverse outcomes are seen. However, when an endogenous chemical, such as 17ss-estradiol (E2), occurs at a concentration sufficient to cause an effect, the threshold is already exceeded. Under these circumstances, exogenous estradiol is not expected to provide a threshold dose. This principle is demonstrated for E2 in the red-eared slider, a turtle with temperature-dependent sex determination. In this species, gonadal sex is determined by egg incubation temperature; female development requires endogenous estrogen produced by elevated temperature. While normal production of females by endogenous estrogens is not an adverse effect, exogenous estrogens can sex reverse presumptive males, which can be an adverse effect. A large dose-response study was conducted using seven doses and a vehicle control (starting n = 300/group); a single E2 dose was applied to the eggshell of recently laid eggs. Animals were sexed after hatching. The incubation temperature chosen, 28.6 degrees C, generates a minority of females. Thus, the criteria for testing the threshold hypothesis were met, i.e., there is evidence that there is endogenous estrogen and that it generates an irreversible response. The lowest E2 dose tested, 400 pg/egg (40 ng/kg), sex reversed 14.4% of the animals, demonstrating very low dose sensitivity. The data were fit with a modified Michaelis-Menten equation, which provided an estimate of 1.7 ng/egg for endogenous estradiol. The median effective dose (ED50) was 5.0 +/- 2.0 ng/egg (95% confidence limits), of which 1.7 ng/egg was endogenous estradiol and 3.3 ng/egg came from the applied estradiol. There was no apparent threshold dose for E2. A smaller replication confirmed these results. These results provide a simple biologically based dose-response model and suggest that chemicals which act mechanistically like E2 may also show no threshold dose. If so, even low environmental concentrations of such chemicals may carry risk for sex reversal.

Animals↗
PubMed1998

Use of Druckrey analysis to quantitatively evaluate the chemopreventive efficacy of N-difluoromethylornithine (DFMO), a prototype proliferation inhibitor.

Druckrey analysis of the results of skin painting TG.AC transgenic mice with three different doses of benzo[a]pyrene was used to obtain quantitative estimates of the in vivo cancer chemopreventive efficacy of N-difluoromethylornithine. The percent decrease in mean rate of subvisible tumor development during the tumor latent period produced by 2000 ppm and 4000 ppm DFMO in the diet was 39% and 50%, respectively. Druckrey analysis was also successfully applied to transformations of published data on human cigarette smokers. The time before onset of lung cancer in 2% of smokers was prolonged 17 weeks for every cigarette per day not smoked. The Druckrey model, of substantiated validity because of the results in human smokers, provides a rapid quantitative screening method applicable to large numbers of candidate chemopreventive agents.

Animals↗
PubMed1998

Procedures for calculating benchmark doses for health risk assessment.

Safety assessment for noncancer health effects generally has been based upon dividing a no observed adverse effect (NOAEL) by uncertainty (safety) factors to provide an acceptable daily intake (ADI) or reference dose (RfD). Since the NOAEL does not utilize all of the available dose-response data, allows higher ADI from poorer experiments, and may have an unknown, unacceptable level of risk, the benchmark dose (BD) with a specified, controlled low level of risk has become popular as an adjunct to the NOAEL or the low observed adverse effect level (LOAEL) in the safety assessment process. The purpose of this paper is to summarize statistical procedures available for calculating BDs and their confidence limits for noncancer endpoints. Procedures are presented and illustrated for quantal (binary), quasicontinuous (proportion), and continuous data. Quasicontinuous data arise in developmental studies where the measure of an effect for a fetus is quantal (normal or abnormal) but the experimental unit is the mother (litter) so that results can be expressed as the proportion of abnormal fetuses per litter. However, the correlation of effects among fetuses within a litter poses some additional statistical problems. Also, developmental studies usually include some continuous measures, such as fetal body weight or length. With continuous data there generally is not a clear demarcation between normal and adverse measurements. In such cases, extremely high and/or low measurements at some designated percentile(s) can be considered abnormal. Then the probability (risk) of abnormal individuals can be estimated as a function of dose. The procedure for estimating a BD with continuous data is illustrated using neurotoxicity data. When multiple measures of adverse effects are available, a BD can be estimated based on a selected endpoint or the appearance of any combination of endpoints. Multivariate procedures are illustrated using developmental and reproductive toxicity data.

Animals↗
PubMed1998

Alternative tests: carcinogenesis as an example.

Acceptance of new tests that are alternatives to currently used toxicology tests is a topic of considerable importance in the field of toxicology. Carcinogenicity testing today normally includes 2-year studies in rats and mice of both sexes, following widely accepted procedures for husbandry; selection of dose levels; pathology and toxicity observations; and statistical interpretation of tumor data. These studies are usually preceded by tests for genetic toxicity and subchronic toxicity studies to select dose levels for the 2-year studies. Although these data are used for quantitative risk assessment, the mechanistic basis for effects is usually unknown. The series of studies is very expensive and requires 5 years or more to conduct. Alternative approaches are being developed that would provide more mechanistic information and hopefully would permit decisions to be made about carcinogenic potential without the need to conduct 2-year studies in rats and mice of both sexes. Decisions could be based on a profile of data rather than on the result of one test. Procedures for regulatory acceptance of new approaches for carcinogenicity testing are critical to future progress.

Animal Testing Alternatives↗
PubMed1997

New directions for predicting carcinogenesis.

Carcinogenicity testing today normally includes conducting 2-yr studies of rats and mice of both sexes and following widely accepted procedures for husbandry, selection of dose levels, pathology and toxicity observations, and statistical interpretation of tumor data. These studies are usually preceded by tests for genetic toxicity and subchronic toxicity studies to select dose levels for the 2-yr studies. While these data are used for quantitative risk assessment, the mechanistic basis for effects is usually unknown, and such series of studies are very expensive and require five or more years to conduct. Alternate approaches are being developed that would provide more mechanistic information and perhaps would permit decisions to be made about carcinogenic potential without the need to conduct 2-yr studies of rats and mice of both sexes. Decisions could be based on a profile of data rather than the result of one test. Regulatory acceptance of new approaches for carcinogenicity testing is critical to future progress in the field of carcinogenesis.

Animals↗
PubMed1996

Significance of DNA adducts at low dose: shortening the time to spontaneous tumor occurrence.

Formation and repair of adducts from DNA-reactive carcinogens as well as induction of genetic changes is expected to be proportional to dose as long as the rates of the enzymatic reactions are proportional to the substrate concentration and as long as the kinetics of cell division are not affected. Deviations from linearity are expected in situations of saturated or induced kinetics and whenever toxicity stimulates regenerative processes and accelerates the fixation and accumulation of mutations resulting from primary DNA lesions. Background DNA damage is postulated to drive the process of carcinogenesis resulting in what is called "spontaneous" tumor formation. Exposure to a low dose of a DNA-reactive carcinogen can result in a dose-dependent acceleration of the spontaneous process but it cannot induce cancer "out of the blue." The shortening of the time to occurrence of a tumor is estimated for different situations using the multistage model. For a tumor which has a high background rate and a large number of steps, life shortening is small, while at a low background incidence rate and a small number of stages, life shortening can be larger. For the majority of tumors, therefore, the approach presented should be able to relieve from the idea that a low dose of a carcinogen could induce cancer early in the life of an individual who without exposure would have lived a much longer, tumor-free life.

Animals↗
PubMed1991

A model-free approach to low-dose extrapolation.

Estimates of risk associated with exposure to low levels of carcinogenic substances present in the environment are generally obtained by linear extrapolation from higher exposure levels at which risks can be estimated directly. In this paper, we examine the scientific basis for the assumption of low-dose linearity in carcinogenic risk assessment and the different statistical methods that have been proposed for linear extrapolation. A model-free approach to linear extrapolation is described and illustrated using epidemiological data on radiation carcinogenesis. The statistical properties of this method are empirically assessed using 572 selected sets of bioassay data.

Carcinogens, Environmental↗
PubMedDate not supplied

Nonneoplastic changes induced in female C3H mice by chronic exposure to diethylstilbestrol or 17 beta-estradiol.

The long-term nonneoplastic effects of estrogenic diets were studied in female C3H/HeJ and C3HeB/FeJ mice. C3H/HeJ mice received diets containing 0, 10, 100, or 500 ppb diethylstilbestrol (DES) or 100, 1000, or 5000 ppb 17 beta-estradiol (E2) from 6 to 110 wk of age. C3HeB/FeJ females were fed diets containing nominal concentrations of 0, 10, 100, or 500 ppb DES from 6 to 136 wk of age. Responses of both strains to DES were qualitatively identical. Histological changes in the reproductive tract induced or increased by DES in both strains and by E2 in C3H/HeJ mice included stromal mucoid changes in the vagina and cervix, epithelial keratinization in the vagina, and glandular hyperplasia in the uterine horns. Increasing doses above 10 ppb DES or 100 ppb E2 increased the prevalence and, in some cases, severity of these responses. Dose-responses to DES for these endpoints were virtually indistinguishable in the two strains. At 10 ppb DES or 100 ppb E2 there were minimal or no observable effects. When the nonneoplastic dose-response data were compared with neoplastic dose-response data previously reported, no consistent relation between doses causing neoplastic and nonneoplastic responses was seen for the two estrogens.

Animals↗
PubMedDate not supplied

An estimation of squamous cell carcinoma risk from ultraviolet radiation emitted by fluorescent lamps.

The risk of squamous cell carcinoma (SCC) from ultraviolet radiation (UV) emitted by unfiltered fluorescent lamps was assessed. The assessment employed a mathematical power model based on human epidemiological data, which relates the SCC incidence in the United States white population to ambient solar UV. The annual numbers of new SCC on anatomical sites chronically exposed to solar UV (head/face/neck and hands) were estimated for indoor workers. Then the number of SCC that may be caused by additional UV exposure from indoor fluorescent lighting was estimated: the lifetime exposure of indoor workers to typical fluorescent lighting (if unfiltered) may add 3.9% (1.6-12%) to the risk from solar UV, resulting in the induction of an additional 1500 (600-4500) SCC per annum in the United States. This calculated projection must be compared with the 110,000 SCC caused by solar exposure. Thus, this analysis suggests there may be a small increased risk of SCC from exposure to UV-emitting fluorescent lamps.

Carcinoma, Squamous Cell↗