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D W Gaylor

Publications and source records attributed to D W Gaylor.

At least 91 records · Page 5Linked to original sources
PubMed1988

Applicability of cancer risk assessment techniques to other toxic effects.

The purpose of this paper is to investigate the applicability of cancer risk assessment techniques to other endpoints. The discussion is limited to the problem of high to low dose extrapolation. Although developed to describe cancer data, the multistage model has a general sigmoidal shape which makes it amenable to describe the dose-response of many non-cancer endpoints. At low doses the multistage model is essentially a general polynomial model. Low-dose linear extrapolation provides an upper limit on convex (curving upward) dose-response curves. Low-dose linearity is expected if exposure to a toxic substance augments a disease process which is already operating in unexposed animals. Incorporation of pharmacokinetic information may prove useful in simplifying dose-response relationships and may result in lower estimates of risk. A descriptive model can be used to estimate a lower confidence limit on a dose expected to produce a disease incidence, for example, of 1% of the animals (LED01). Then, the LED01/100 provides an estimate of the dose for which the risk is estimated to be less than 10(-4). It appears that some of the techniques used for cancer risk assessment can be used or modified for quantal non-cancer endpoints.

Animals↗
PubMed1987

Using average lifetime dose rate for intermittent exposures to carcinogens.

The effect of using the average dose rate over a lifetime as a representative measure of exposure to carcinogens is investigated by comparing the true theoretical multistage intermittent-dosing lifetime low-dose excess risk to the theoretical multistage continuous-dosing lifetime risk corresponding to the average lifetime dose rate. It is concluded that low-dose risk estimates based on the average lifetime dose rate may overestimate the true risk by several orders of magnitude, but that they never underestimate the true risk by more than a factor of k/r, where k is the total number of stages in the multistage model and r is the number of stages that are dose-related.

Carcinogens↗
PubMed1987

Carcinogenic risk assessment: comparison of estimated safe doses for rats and mice.

Data from the National Cancer Institute/National Toxicology Program (NCI/NTP) carcinogenesis bioassays were examined to compare cancer risks in rats and mice. Only those bioassays where chemicals were administered orally were used. The ratios for rats to mice of the virtually safe dose (VSD) levels associated with a risk of 10(-6) were compared. Comparisons of the ratios were made for those chemicals that NCI/NTP determined to be carcinogenic in at least one species and that showed a dose response trend in the same sex at the same tissue/organ site in the other species. In all, 69 comparisons from 38 carcinogens were performed. The overall geometric mean of the VSD ratios is 1.27 in terms of concentration (ppm); the mean and the standard deviation in logarithm are 0.24 and 1.83, respectively. The VSD ratios vary from 1:51 to 49:1. Without the restriction of the same sex and site, the geometric mean of the minimum VSDs is 1.38, and the standard deviation in logarithm is 1.79. By directly comparing the VSDs for rats and mice (as they are performed for risk assessment), this study showed a probability of 0.10 that the ratio of VSDs is greater than 10, and the ratio is greater than 20 with a probability of 0.05 when a chemical is carcinogenic in both species.

Animals↗
PubMed1987

Statistical variation of selected clinical pathological and biochemical measurements in rodents.

The variability in clinical pathological and biochemical measurements among replicates is often greater than the effects under study. To minimize the effects of this variability, it is recommended that replicated concurrent analyses (randomized blocks) of groups of animals be used. That is, some samples from each of the groups of animals to be compared are analyzed at the same time. This process is replicated until a sufficient number of animals are sampled. If replicated concurrent analyses are not conducted and clinical measurements are made at different times for different groups of animals, the biases may be large. Clinical data were examined from several experiments to illustrate that the problems of clinical measurements are not confined to a particular endpoint, species, or sex. In one case, four times as many animals would have been required using nonconcurrent analyses to achieve the same precision as for concurrent analyses. Permutation analyses of two of the data sets indicate that statistical conclusions concerning the comparison of average clinical levels in different groups of animals would have been incorrect, falsely indicating higher or lower levels in a group over one-half of the time with nonconcurrent analyses.

Alanine Transaminase↗
PubMed1986

The effects of saccharin on the development of neoplastic lesions initiated with N-methyl-N-nitrosourea in the rat urothelium.

Saccharin has been reported to induce urinary bladder tumors in multigeneration rat feeding studies and to promote bladder carcinogenesis in rats initiated with known bladder carcinogens. To examine the dose-dependent effects of saccharin on tumor promotion, sodium saccharin was administered at six levels in the diet (5.0, 2.5, 1.0, 0.5, 0.1, and 0%) to female Sprague-Dawley rats which had received, by trans-urethral instillation into the bladder, either a single dose of saline or an initiating dose of N-methyl-N-nitrosourea (MNU), a potent direct-acting carcinogen. Additional groups with and without MNU treatment received sodium saccharin (2%) in the drinking water, acid-saccharin (5%) in the diet, or MNU, four weekly doses, as a positive control. Histopathologic examination of the urinary bladders from dead and moribund animals and from animals sacrificed after 102 weeks on dose was performed, and benign papillomas were commonly observed in those animals given MNU. A statistical analysis of the lesions indicated an increase in tumor incidence and a decrease in time to tumor with increasing saccharin dose in dead and moribund animals. This response was observed in the dose series of 0 to 2.5% saccharin in the diet. Dead and moribund animals which had received 5% sodium saccharin exhibited few tumors. An increasing incidence of tumors in MNU-treated control animals was observed during the final weeks of the study. Although this increase in background tumors in senescent animals complicated the interpretation of the total tumor incidences, the results in dead and moribund animals (about 60% of the total) indicated that saccharin served as a tumor promoter in this two-stage carcinogenesis model system by decreasing the latency period of the lesions.

Animals↗
PubMed1986

The use of decision-theoretic approach in regulating toxicity.

This paper presents a general decision model for quantitative risk analysis to help in solving the problem of setting the optimal exposure level of a potential carcinogen in regulatory decision-making. This model consists of a probability function and two loss functions. The probability function describes the dose-response relationship for a potential carcinogen at various exposure levels. The two loss functions include the cost of using a potential carcinogen, e.g., health loss, and the cost of not using the compound, e.g., economic loss. Using the principle of minimum expected loss, a fundamental formula for setting the optimal beneficial dose level is derived. The formula equates the probability function to a ratio of loss functions. The general form of loss functions is described in the paper. Under certain conditions, the current approach for quantitative risk assessment is a special situation of this general model.

Carcinogens↗
PubMed1986

Final report of the Color Additive Scientific Review Panel.

The Color Additives Scientific Review Panel considered whether there was information sufficient to perform a carcinogenic risk assessment on the colors D&C Red No. 19 (R-19), D&C Red No. 37 (R-37), D&C Orange No. 17 (O-17), D&C Red No. 9 (R-9), D&C Red No. 8 (R-8) and FD&C Red No. 3 (R-3) and to evaluate the assessments sent to FDA as part of the petitions for use of the colors for drug and external uses by the Cosmetic, Toiletry and Fragrance Association (CTFA). There is a lack of human data concerning the colors for making a human health assessment, so the assessments are based upon the extrapolation of animal data. The risk assessments are determined for exposure to single chemicals. Excluded from consideration are possible effects from exposure to multiple chemicals, such as co-carcinogenesis, promotion, synergism, antagonism, etc. In the light of recent efforts in establishing a consensus in risk assessment, the Panel has determined that the CTFA assessments for R-10, O-17, and R-9 are consistent with present acceptable usages, although it questions some of the assumptions used in the assessments. The Panel identified a number of general assumptions made, and discusses their validity, their impact on total uncertainty, and the potential options to address the gaps in understanding that necessitate the assumption. The Panel also derived revised risk estimates using more "reasonable" assumptions than "worst-case" situations, for 90th percentile and average exposure. For those assumptions that are easily quantifiable, the Panel's estimates are less than an order of magnitude lower than the CTFA risk estimates, indicating that the underestimates and overestimates of the CTFA risk estimates tend to balance each other. The impact of most of the assumptions is not quantifiable. The assessment for R-3 is complicated by the fact that there is no good skin penetrance study for this color. It was assumed that the penetrance is similar to that of another water-soluble xanthene color, R-19. It is expected that the absorption of the color is not likely to exceed that of the smaller molecule, R-19. Therefore, the risk estimates are similar to the CTFA estimates, but with different reasoning. The estimates for R-8 and R-37 are different from the others in that there is a lack of any exposure or toxicological information on these colors.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Relative potency of chemical carcinogens in rodents.

Extensive carcinogenesis data compiled by Gold et al. for 770 compounds tested in 2944 chronic bioassays in animals provided an opportunity to compare cancer rates across animal species for a wide variety of compounds administered by various routes of exposure. The comparisons in this paper are restricted to the most frequently tested species: rats, mice, and hamsters. When sufficient experimental data exist, Gold et al. provide estimates of the TD50 (the chronic dose rate expressed in mg/kg body weight/day which halves the actuarially adjusted percentage of tumor-free animals at the end of a standard lifetime experiment). Since the current practice generally is to base risk assessments upon the data set producing the highest cancer risk, the ratio of the minimum TD50's provides a measure of the relative potency between two species for each compound administered to animals by the same route. The geometric means of the ratios of minimum TD50's for rats:mice are 1/2.2 and 1/1.3 for diet and gavage, respectively. A mean ratio for rats: mice of 1/1.48 is obtained for compounds administered in the diet when the tumor site is the liver for both species. In general the minimum TD50 is lowest for the rat and highest for the hamster. Although limited data are available for inhalation studies, this route of administration resulted in the poorest agreement between rats and mice. In general, comparisons of minimum TD50's across the three rodent species are generally within a factor of 100 for a wide variety of compounds.

Administration, Inhalation↗
PubMed1986

Standardized tumor rates for chronic bioassays.

If crude experimental proportions of animals with tumors from chronic bioassays for carcinogenicity are used for low-dose extrapolation in a risk analysis, different dose-specific patterns of mortality due to competing risks can bias the results. In order to adjust tumor rates for differential mortality across dose groups, Farmer, Kodell, and Gaylor (1982, Risk Analysis 2, 27-34) recommended using nonparametric estimates of probability distributions of times to onset of tumors, with competing causes of death removed, when performing a risk analysis. This paper extends the approach of Farmer et al. by proposing a method for adjusting tumor rates to reflect lifetime or near-lifetime tumor incidences that would be obtained if all dose groups experienced the control mortality rate from causes other than the tumor of interest. Thus, natural mortality due to competing risks is explicitly included, rather than removed. The proposed standardized tumor rates are calculated as a summation of adjusted age-specific probabilities of dying with a tumor during the course of an animal bioassay for carcinogenicity plus the probability of being alive with a tumor at the terminal sacrifice.

Animals↗
PubMed1985

Chronic toxicity and carcinogenicity studies of gentian violet in mice.

Gentian violet is a dye belonging to a chemical class known as the di- and triaminophenylmethanes. Although it has been used for many years for the control of fungal and intestinal parasites, for various uses in veterinary medicine, and as an additive to the feed of chickens to inhibit propagation of mold and fungus, very few long-term toxicity data are available. A life span dosing study of gentian violet in the diet of 720 males and 720 females of B6C3F1 mice (C57BL/6 X C3H) at dose levels of 0, 100, 300, and 600 ppm was done to determine its toxicity and carcinogenicity. Sacrifices were conducted after 12, 18, and 24 months of continuous dosing. There was no effect on food consumption or body weight gain; however, a dose effect was noted for mortality rates. Mortality (adjusted for sacrifices) in the controls of both sexes was less than 15% at 24 months, but was approximately 64% in the females and 23% in the males given the high dose. Females appeared to be more susceptible than males. A positive dose response for hepatocellular carcinoma was noted in males at 24 months and in females at 18 and 24 months. Statistical tests for dose-related trends with respect to mortality due to liver neoplasms, prevalence of liver neoplasms, and time to onset of liver neoplasms showed positive trends in both males and females. Other dose-related toxicological responses, particularly in the female mice, included erythropoiesis in the spleen, atrophy of the ovaries, adenoma of the Harderian gland, and the presence of type A reticulum cell sarcomas in the urinary bladder, uterus, ovaries, and vagina. The estimation of risk of 10(-6) over background for malignant liver neoplasms using linear extrapolations showed a lower bound on the virtually safe dose (VSD) to be 2 ppb for the female mice and 1 ppb for the male mice. For benign and malignant liver tumors together, the lower bound on the VSD was essentially the same as for malignant liver neoplasm alone. Under the conditions of the experiment described above, gentian violet appears to be a carcinogen in mice at several different organ sites.

Animals↗
PubMed1985

Carcinogenesis of 4-aminobiphenyl in BALB/cStCrlfC3Hf/Nctr mice.

Male and female (840 each) BALB/cStCrlfC3Hf/Nctr mice were given 0, 7, 14, 28, 55, 110 and 220, and 0, 7, 19, 38, 75, 150 and 300 ppm, respectively, of 4-aminobiphenyl in their drinking water. Necropsies on killed animals were performed at 13, 26, 39, 52 and 96 weeks on dose. Dose-related neoplasms were angiosarcomas, bladder urothelial carcinomas and hepatocellular neoplasms. The non-neoplastic dose-related lesions were left atrial thrombosis, bladder urothelial hyperplasia, splenic hemosiderosis and splenic erythropoiesis. The incidences of bladder carcinoma and atrial thrombosis were higher in the males and the incidences of hepatocellular neoplasms and angiosarcomas were higher in the females.

Aminobiphenyl Compounds↗
PubMed1985

Influence of total dose and dose rate in carcinogenicity studies.

One element of the ED01 Study contained a group of animals that were dosed with 2-acetylaminofluorene for 9, 12, 15, 18, or 24 mo and then sacrificed at 18 or 24 mo. This provided data to compare the relative effects on carcinogenicity of dose rate versus total dose. The prevalence of liver and bladder tumors were used as the comparison. Animals receiving similar total doses but over a different length of time (different dose rates) were compared at the 18- and 24-mo sacrifices. When the total doses were similar, the higher dose rates for shorter time periods induced a higher prevalence of tumors. Results were more consistent for bladder tumors than for liver tumors, although the same trends were noted for both endpoints. Those groups dosed at higher rates but for fewer months had a generally higher prevalence than those receiving similar total doses but at lower rates for more months. This data from the ED01 Study illustrates the importance of experimental design, dosing regime, length of study time, and age of the animals at time of dosing in respect of calculation of risk.

2-Acetylaminofluorene↗
PubMed1985

Experimental design of bioassays for screening and low dose extrapolation.

Relatively high doses of chemicals generally are employed in animal bioassays to detect potential carcinogens with relatively small numbers of animals. The problem investigated here is the development of experimental designs which are effective for high to low dose extrapolation for tumor incidence as well as for screening (detecting) carcinogens. Several experimental designs are compared over a wide range of different dose response curves. Linear extrapolation is used below the experimental data range to establish an upper bound on carcinogenic risk at low doses. The goal is to find experimental designs which minimize the upper bound on low dose risk estimates (i.e., maximize the allowable dose for a given level of risk). The maximum tolerated dose (MTD) is employed for screening purposes. Among the designs investigated, experiments with doses at the MTD, 1/2 MTD, 1/4 MTD, and controls generally provide relatively good data for low dose extrapolation with relatively good power for detecting carcinogens. For this design, equal numbers of animals per dose level perform as well as unequal allocations.

Animals↗
PubMed1985

Occurrence of tumors among litters of BALB/c female mice.

In the application of statistical techniques to tumor incidence data it is generally assumed that animals respond independently with regard to tumor occurrence, with littermates being no more alike than are animals from different litters. Data for nine different types of tumors from the large ED01 study conducted at the National Center for Toxicological Research were used to compare tumor prevalence rates among litters with the tumor rates expected under the assumption of homogeneity of tumor rates among litters. These data did not provide sufficient evidence to reject the assumption of homogeneity of tumor prevalence rates among litters of inbred female BALB/c mice for either spontaneously occurring tumors or bladder tumors produced by exposure to 2-acetylaminofluorene (CAS: 53-96-3). However, there does appear to be a difference in liver tumor prevalence rates among litters at 24 months of age. Thus litter effects are a factor that should be considered in the assignment of animals to treatment groups in carcinogenesis studies.

2-Acetylaminofluorene↗
PubMed1984

The role of maternal diet in the developmental toxicology of ethanol.

A commonly observed result of ethanol administration to experimental animals is a reduction in voluntary dietary intake. The purpose of this investigation was to examine the role of this reduction in the developmental/reproductive toxicity of ethanol. To achieve this objective, female C3H mice were administered one of the following diets from Day 0 to Day 17 of pregnancy: (1) liquid diet, (2) liquid diet plus 4.1% w/v ethanol, (3) an amount of liquid diet equal to that consumed by the liquid diet plus 4.1% w/v ethanol group, i.e., pair-fed, (4) liquid diet fortified with protein, fats, carbohydrates, vitamins, and minerals, or (5) fortified diet plus 4.1% w/v ethanol. An important aspect of this experiment was the 2 X 2 factorial design, which permitted the analysis of the effects of ethanol consumption, diet intake reduction, and potential interactions between these two factors. After maternal death on Day 17 of gestation, fetuses were examined for evidence of alterations in growth and/or development. Analysis of the results revealed that decreased dietary intake, but not ethanol consumption resulted in a decrease in fertility, maternal pregnancy weight gain, and litter size. In contrast, both decreased dietary intake and ethanol consumption significantly inhibited fetal growth and development. However, no interaction between these two factors was demonstrated, indicating that ethanol's fetotoxic effects occurred, regardless of maternal dietary intake. We conclude that, depending on the endpoint examined, maternal nutrition plays a key role in experimental ethanol fetotoxicity. However, this agent is fetotoxic, even in the well-nourished animal.

Animals↗
PubMed1984

Benzidine dihydrochloride: risk assessment.

Benzidine, recognized as a bladder carcinogen in man and as a liver carcinogen in experimental animals, is the chemical basis of as many as 200 commercial dyes. Physiological processes can metabolize these dyes to release benzidine, thereby creating a potential exposure hazard. To assess this hazard, both sexes of F1 hybrid (genetically homogeneous) and monohybrid (genetically heterogeneous) mice from a BALB/c male and C57BL/6 female cross were exposed for their respective lifespans to benzidine dihydrochloride in their drinking water at concentrations of 0, 30, 40, 60, 80, 120, and 160 ppm for males, and 0, 20, 30, 40, 60, 80, and 120 ppm for females. Animals were removed from the study when they were dead or moribund. This study was terminated after 33 months of exposure. Using the endpoint of hepatocellular adenomas and carcinomas, the Armitage Doll multistage model was used to describe the tumor rates in the experimental dose range and to obtain the upper confidence level on tumor rates. Linear interpolation was used between zero dose and the upper confidence level of the lowest experimental dosage for predicting potential low dose tumor rates. Dose-response effects on body weight, survival, and liver neoplasms were noted in both stocks. For each of the endpoints, the females were more susceptible than males and the F1 (homogeneous) stock was more susceptible than the monohybrid cross (heterogeneous). The calculated virtually "safe" dose predicted to produce less than one per million F1 female mice with a liver tumor is 0.045 ppb. One part per billion of benzidine dihydrochloride in the drinking water of these mice is estimated to produce liver tumors in less than 2.23 mice per 100,000 population.

Animals↗
PubMed1983

Statistical criteria for evaluating chemicals as positive or negative in the hepatocyte/DNA repair assay.

The usefulness of the hepatocyte/DNA repair assay was enhanced when statistical techniques were applied to the evaluation of a chemical as positive or negative. Using our test procedure, we are 95% confident that the false positive rate is less than 1% if the net nuclear grain count for the test chemical is 3 counts higher than the solvent control for the same animal. Additionally, quantitation of the proportion of cells in repair should be used to corroborate the results of the net nuclear grain count and is recommended for inclusion in the criteria for evaluating a chemical.

Animals↗