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D W Gaylor

Publications and source records attributed to D W Gaylor.

At least 73 records · Page 4Linked to original sources
PubMed1991

Mathematical modeling of reproductive and developmental toxic effects for quantitative risk assessment.

A new mathematical dose-response model for reproductive and developmental risk assessment is proposed. The model includes the possibility of an exposure threshold as well as a litter-size effect. Correlation of responses of offspring from the same litter is taken into account through the use of the beta-binomial distribution. Confidence limits for low-dose extrapolation are based on the asymptotic distribution of the likelihood ratio. An empirical comparison of the proposed procedure to that of Rai and Van Ryzin demonstrates the improvement that can be achieved with the new procedure.

Animals↗
PubMed1991

Analysis of trinomial responses from reproductive and developmental toxicity experiments.

This paper presents a Dirichlet-trinomial distribution for modelling data obtained from reproductive and developmental studies. The common endpoints for the evaluation of reproductive and developmental toxic effects are the number of dead fetuses, the number of malformed fetuses, and the number of normal fetuses for each litter. With current statistical methods for the evaluation of reproductive and developmental effects, the effect on the number of deaths and the effect on the number of malformations are analyzed separately. The Dirichlet-trinomial model provides a procedure for the analysis of multiple endpoints simultaneously. This proposed Dirichlet-trinomial model is a generalization of the beta-binomial model that has been used for handling the litter effect in reproductive and developmental experiments. Likelihood ratio tests for differences in the number of deaths, the number of malformations, and the number of normals among dosed and control groups are derived. The proposed test procedure based on the Dirichlet-trinomial model is compared with that based on the beta-binomial model with an application to a real data set.

Abnormalities, Drug-Induced↗
PubMed1990

Chronic toxicity/carcinogenicity studies of sulphamethazine in Fischer 344/N rats: two-generation exposure.

Fischer 344 rats were given 10, 40, 600, 1200 or 2400 ppm sulphamethazine (SMZ) in the diet to determine the toxicity and potential carcinogenicity of SMZ. There were 225 rats of each sex in the control groups and 135 of each sex in each dose group. Animals were killed after 3, 12, 18 or 24 months of continuous dosing. Body weights, feed consumption, clinical observations, organ weights and histopathology data were collected. A slight decrease in body-weight gain was observed in the high-dose groups compared with the controls. No difference in feed consumption was found between the control and dosed rats. Mortality was inversely related to SMZ dose, especially in females, that is mortality was highest in the controls and decreased as the dose of SMZ increased. A statistically significant dose-related increase in the incidence of follicular cell adenocarcinomas of the thyroid gland was observed in the animals killed after 24 months. The incidences of non-neoplastic lesions of the thyroid gland in treated animals were significantly higher among treated animals than among controls; these lesions included follicular cell hyperplasia, follicular cell focal cellular change and multilocular cysts. The incidences of retinal atrophy, atrophy of the acinar pancreas (males), and dilatation of the uterine lumen also increased with increasing SMZ dose.

Adenocarcinoma↗
PubMed1990

Estimation of the joint risk for multiple-compound exposure based on single-compound experiments.

In the absence of data from multiple-compound exposure experiments, the health risk from exposure to a mixture of chemical carcinogens is generally based on the results of the individual single-compound experiments. A procedure to obtain an upper confidence limit on the total risk is proposed under the assumption that total risk for the mixture is additive. It is shown that the current practice of simply summing the individual upper-confidence-limit risk estimates as the upper-confidence-limit estimate on the total excess risk of the mixture may overestimate the true upper bound. In general, if the individual upper-confidence-limit risk estimates are on the same order of magnitude, the proposed method gives a smaller upper-confidence-limit risk estimate than the estimate based on summing the individual upper-confidence-limit estimates; the difference increases as the number of carcinogenic components increases.

Animals↗
PubMed1990

Risk assessment for neurotoxic effects.

Regulation of neurotoxicants is generally based on setting allowable doses (exposures) by dividing a no observed adverse effect level (NOAEL) by uncertainty factors that hopefully account for interspecies and intraspecies differences for extrapolations of experimental results obtained in animals to humans. This procedure makes no use of estimates of risk as a function of dose or does it acknowledge any risk at the NOAEL. The purpose of this paper is to illustrate how bioassay data can be used to estimate the risk of neurotoxic effects as a function of dose. In the absence of direct measurements of neurotoxic effects, biomarkers associated with neurotoxic effects can be used as measures of toxicity. In the absence of a definition of an adverse effect, an abnormal level for a measure of toxicity can be established which occurs only in a small fraction of a population which is not exposed to the substance under investigation. Risk is defined as the proportion of a population whose levels of a measure of toxicity equal or exceeds the abnormal level of the measure under study. The procedure is illustrated using data for neurochemical, neurohistological, and behavioral effects of methylenedioxymethamphetamine (MDMA) administered to rats or monkeys. This procedure is more versatile than the NOAEL/uncertainty factor approach since it provides estimates of risk as a function of dose of a potential neurotoxic substance.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Workshop on risk assessment in reproductive and developmental toxicology: addressing the assumptions and identifying the research needs.

The risk assessment process is an imprecise procedure aimed at determining a toxicant exposure level with an acceptable risk to the human population. The lack of precision is due to the uncertainties in the assumptions that must be made due to the lack of specific scientific information or knowledge of how to use certain types of data. Unfortunately, every necessary piece of information cannot be obtained for every chemical requiring a risk assessment. In order to better identify and understand some of the assumptions that are made in the risk assessment of reproductive and developmental toxicants, a workshop was organized to specifically define the assumptions underlying the risk assessments for seven specific toxicants (dibromochloropropane, dioxin, glycol ethers, heptachlor, lead, tetrahydrocannabinol, and vitamin A) and to determine the potential research which would reduce the uncertainty associated with making those assumptions. The major assumptions discussed centered around the topics of heterogeneous populations, thresholds, safety factors, exposure assessment, quantitative structure-activity relationships, and mechanisms. This report is the summary of the workshop discussions.

Animals↗
PubMed1989

Comparison of teratogenic and carcinogenic risks.

Risk assessment for teratogens has received much less attention than carcinogens. This may be due in part to the lack of biologically based dose-response models for teratogens. Also, there appears to be a perception that cancer risks far exceed teratogenic risks for most chemicals. This perception may be due in large part to the stringent practice of using conservative procedures to restrict cancer risk estimates to one in 100,000 or lower whereas procedures used to restrict teratogens may result in much higher risks. The purpose of this paper is to compare estimates of teratogenic and carcinogenic risks for chemicals when both effects occur in the same animal species. Similar procedures are employed here to obtain teratogenic and carcinogenic risk estimates for nine chemicals. When a similar standard of risk is applied to both effects, the relative potency of teratogens to carcinogens varied from an order of magnitude lower to an order of magnitude higher for these nine chemicals.

Animals↗
PubMed1989

Preliminary estimates of the virtually safe dose for tumors obtained from the maximum tolerated dose.

The purpose of this paper was to examine the correlation between the maximum tolerated dose (MTD) and the low-dose estimate of the virtually safe dose (VSD) for animal carcinogens. Chronic bioassay results from the National Cancer Institute/National Toxicology Program carcinogenesis screening program were used. Estimates of the VSD were obtained by linear low-dose extrapolation for which an adequate dose-response relationship existed at the same tumor site in the same sex for both rats and mice. Estimates of the VSD were compared with the MTD for 69 tumor sites from 38 chemicals for rats and mice. The MTDs ranged from high to low toxicity (1 ppb to 4.4% in the diet). The overall geometric mean of the ratio of the MTD to the VSD corresponding to a maximum estimated risk of 10(-6) was 3.8 x 10(5). Of the 138 cases, only 3 cases were more than a factor of 10 from the mean ratio. This suggested that a quick estimate of the VSD could be obtained by dividing the MTD, obtained from a subchronic study, by 400,000. Further, if the human exposure is less than 10(-7) X MTD, the estimated risk is likely to be negligible even if the chemical is a carcinogen. It may not be worthwhile to conduct a chronic bioassay for the purpose of demonstrating a negligible risk, if the chemical is likely to be carcinogenic, unless the human exposure is extremely low.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

A note on the role of background tumor incidence in risk assessment for carcinogens.

The extrapolation of animal bioassay data to humans for the purpose of estimating risk from food additives, drugs, pesticides, etc. is still the primary approach to carcinogenic risk assessment. When the extrapolation is based on tumor data with high background incidence (e.g., hepatocellular tumors in rodents), its direct relevance to the human situation is sometimes questioned. This paper suggests a method for adjusting the acceptable excess risk level for humans according to the background incidence of the tumor type used for extrapolating from animals to humans. Application of the suggested "fixed relative risk" extrapolation method in setting acceptable low-risk exposure levels for humans is illustrated for methylene chloride.

Carcinogens↗
PubMed1989

Chronic toxicity/carcinogenicity studies of sulphamethazine in B6C3F1 mice.

A chronic feeding study was carried out in B6C3F1 mice with sulphamethazine (SMZ). The test substance was administered in the diet at dose levels of 0 (control), 300, 600, 1200, 2400 and 4800 ppm for 24 months. Mice were killed after 12, 18 and 24 months of continuous dosing. Body weights and food consumption were measured weekly, and mortality was recorded daily. All animals received a complete necropsy and histopathological examination, the results of which were analysed statistically. A slight decrease in body-weight gain was noted for mice of all dose groups with females showing the greater effect. Food consumption based on g food/g average body weight was relatively constant among the controls and various dose groups. The mortality rate for males and females of the control groups (8 and 8%, respectively) was higher than that for males and females of some of the higher dose groups. Neoplastic lesions associated with the ingestion of SMZ in the diet included follicular cell adenomas of the thyroid gland. At the 24-month necropsy, the incidence of this lesion for males and females of the 4800-ppm dose groups was 33 and 26%, respectively. Non-neoplastic dose-related lesions observed in both males and females included follicular cell hyperplasia (diffuse and focal) of the thyroid gland, haematopoietic cell proliferation of the spleen and pigmentation of the spleen. In females, pigmentation of the lymph nodes and hyperplasia of the mammary gland were also noted.

Adenoma↗
PubMed1989

Chronic toxicity/carcinogenicity studies of gentian violet in Fischer 344 rats: two-generation exposure.

A chronic feeding study was carried out in the F1a generation of dosed Fischer 344 rats of both sexes with gentian violet (GV). The test substance was administered in the diet to 570 male and 570 female rats at dose levels of 0 (control), 100, 300 and 600 ppm for 24 months. Rats were killed and necropsied after 12, 18 and 24 months of continuous dosing. Measurements of body weights, food consumption (and dose rate) and mortality and the results of histopathological examination were analysed statistically. Male and female rats fed 600 ppm GV for 24 months showed a decrease in body weights. Average food consumption based on g food/kg average body weight was essentially equal in all groups. Mortality at the end of the study (24 months) was approximately 33% in the controls for both males and females and approximately 66% in females of the high-dose group and 48 and 39% in males of the mid- and high-dose groups, respectively. All dose-related neoplastic pathology was noted at the final necropsy. Following 24 months of dosing, there was a significant difference from the controls in the incidence of follicular cell adenocarcinoma of the thyroid gland for both males (600 ppm GV) and females (300 and 600 ppm GV). Although the incidences were very low, statistical analysis showed a significant difference from the controls for hepatocellular adenomas in the mid-dose group of the females and the mid- and high-dose groups of the males. A dose-time-related incidence of mononuclear cell leukaemia was also noted in the females. There was high background incidence of the leukaemia. Several non-neoplastic dose-related lesions were observed in both males and females, principally in the 18- and 24-month necropsies. Almost all of these lesions were focal changes in the liver, many of which were probably related to the mononuclear cell leukaemia.

Animals↗
PubMed1989

Multistrain experiments for screening toxic substances.

The advantages of using homogeneous experimental groups (inbred animal strains) and of using multiple groups within an experiment, based on the power of the Mantel-Haenszel test, were investigated. A simulation experiment was performed to empirically calculate the power of a one-sided Mantel-Haenszel test for multistrain experiments. In each case, the power of the multistrain experiment was compared to the (empirical) expected value, over strains, of the power where each strain is tested individually. In the simulation, use of subgroups, each having different response rates, resulted in an increase in power where a chemical exposure caused an average increase of effects in 10% or more of the animals across strains.

Animals↗
PubMed1989

Quantitative risk analysis for quantal reproductive and developmental effects.

Animal experiments are generally conducted at higher dose levels than anticipated human dose levels in order to elicit otherwise subtle changes in reproduction or developmental effects with relatively few animals. Based on animal data, regulatory strategy generally has been to postulate a no-observed-effect level (NOEL) for toxic effects and to divide this by a safety factor, usually 100, to establish acceptable levels for humans. Various authors have discussed the shortcomings of using NOEL and have suggested the use of an estimable effect level determined from a dose-response curve fitted to bioassay data, e.g., the dose at which 1% of the animals are adversely affected, and employing some form of conservative low dose extrapolation to control risks at lower doses. In this paper, 10 sets of bioassay data on fetal mortality or anomalies were used to compare the estimated upper limits of risk estimated at the NOEL/100 and the lower 95% confidence limit estimate of the dose producing adverse effects in 1% of the embryonic implants or fetuses divided by 100 (LED01/100). The latter quantity is expected to result in a risk (proportion affected) of less than 10(-4) (1 in 10,000). The estimated upper limits of risk associated with the NOEL/100 were from 2 x 10(-4) to 6 x 10(-4) for the 10 data sets investigated.

Abnormalities, Drug-Induced↗
PubMed1988

Estimates of the risk of bladder tumor promotion by saccharin in rats.

Tumor data from an initiation-promotion bioassay in rats are used to illustrate how urinary bladder tumor risk estimates can be modified to reflect tumor promotion by saccharin. Assuming equal carcinogenic potency in humans and rats, the estimated human risk is equal to the probability of tumors in rats due to saccharin promotion following administration of an initiator times the ratio of the proportion of humans that are initiated to the proportion of initiated rats. The proportion of initiated humans may be somewhere between the proportion of deaths due to bladder cancer in the U.S. population, 0.005, and 1.0. The proportion of initiated animals in the bioassay may be somewhere between the proportion of animals with bladder tumors, 0.41, as observed in an initiated group, and 1.0. Hence, the ratio of the proportion of initiated humans to animals may be between 0.005 and 2.4. Then, the risk of bladder tumors is estimated to be between 0.005 and 2.4 times the estimated risk of tumors in rats promoted by saccharin following administration of an initiator. An upper limit on bladder tumor risk is estimated to be between 0.00038 and 0.18 times the percentage of saccharin in the diet. If a threshold dose exists for saccharin bladder tumor promotion which is above the saccharin consumption level of all humans, then the risk is zero.

Animals↗
PubMed1988

Issues in qualitative and quantitative risk analysis for developmental toxicology.

The qualitative and quantitative evaluation of risk in developmental toxicology has been discussed in several recent publications. A number of issues still are to be resolved in this area. The qualitative evaluation and interpretation of end points in developmental toxicology depends on an understanding of the biological events leading to the end points observed, the relationships among end points, and their relationship to dose and to maternal toxicity. The interpretation of these end points is also affected by the statistical power of the experiments used for detecting the various end points observed. The quantitative risk assessment attempts to estimate human risk for developmental toxicity as a function of dose. The current approach is to apply safety (uncertainty) factors to the no observed effect level (NOEL). An alternative presented and discussed here is to model the experimental data and apply a safety factor to an estimated risk level to achieve an "acceptable" level of risk. In cases where the dose-response curves upward, this approach provides a conservative estimate of risk. This procedure does not preclude the existence of a threshold dose. More research is needed to develop appropriate dose-response models that can provide better estimates for low-dose extrapolation of developmental effects.

Animals↗
PubMed1988

Using the biological two-stage model to assess risk from short-term exposures.

Two assumptions used in risk assessment are investigated: (1) the assumption of fraction of lifetime dose rate assumes that the risk from a fractional lifetime exposure at a given dose rate is equal to the risk from full lifetime exposure at that same fraction of the given dose rate; (2) the assumption of fraction of lifetime risk assumes that the risk from a fractional lifetime exposure at a given dose rate is equal to that same fraction of the risk from full lifetime exposure at the same dose rate. These two assumptions are equivalent when risk is a linear function of dose. Thus both can be thought of as generalizations of the assumption that cancer risk is proportional to the total accumulated lifetime dose (or average daily dose), which is often made to assess the risk from short-term exposures. In this paper, the age-specific cumulative hazard functions are derived using the two-stage model developed by Moolgavkar, Venzon, and Knudson for situations when the exposure occurs during a single period or a single instant. The two assumptions described above are examined for three types of carcinogens, initiator, completer, and promoter, in the context of the model. For initiator and completer, these two assumptions are equivalent in the low-dose region; for a promoter, using the fraction of lifetime risk assumption is generally more conservative than that of the fraction of lifetime dose rate assumption. Tables are constructed to show that the use of either the fraction of lifetime dose rate assumption or the fraction lifetime risk assumption can both underestimate and overestimate the true risk for the three types of carcinogens.

Age Factors↗