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Biomedical subjects

D W Gaylor

Publications and source records attributed to D W Gaylor.

At least 37 records · Page 2Linked to original sources
PubMed1998

A comparison of the tumors induced by coal tar and benzo[a]pyrene in a 2-year bioassay.

The tumorigenicity of two coal tar mixtures was compared to that of benzo[a]pyrene after 2 years of feeding. Mixture 1, a composite of coal tar from seven coal gasification plant waste sites, was fed to female B6C3F1 mice (48 mice per group) for 2 years at doses of 0.0, 0.01, 0.03, 0.1, 0.3, 0.6 and 1.0%. Mixture 2, which was composed of coal tar from two of the seven waste sites and another site having a high benzo[a]pyrene content, was fed at doses of 0.0, 0.03, 0.1 and 0.3%. Additional groups of mice were fed 0, 5, 25 and 100 ppm benzo[a]pyrene. The coal tar diets induced a dose-related increase in hepatocellular adenomas and carcinomas, alveolar/bronchiolar adenomas and carcinomas, forestomach squamous epithelial papillomas and carcinomas, small intestine adenocarcinomas, histiocytic sarcomas, hemangiosarcomas in multiple organs and sarcomas. Benzo[a]pyrene treatment resulted in an increased incidence of papillomas and/or carcinomas of the forestomach, esophagus and tongue. A comparison of the results indicated that the benzo[a]pyrene in the coal tar diets could be responsible for the forestomach tumors. In contrast, the lung and liver tumors appeared to be due to other genotoxic components contained within the coal tar mixture, while the small intestine tumors resulted from chemically-induced cell proliferation that occurred at high doses of coal tar.

Adenoma↗
PubMed1998

Upregulation of apoptosis with dietary restriction: implications for carcinogenesis and aging.

The maintenance of cell number homeostasis in normal tissues reflects a highly regulated balance between the rates of cell proliferation and cell death. Under pathologic conditions such as exposure to cytotoxic, genotoxic, or nongenotoxic agents, an imbalance in these rates may indicate subsequent risk of carcinogenesis. Apoptotic cell death, as opposed to necrotic cell death, provides a protective mechanism by selective elimination of senescent, preneoplastic, or superfluous cells that could negatively affect normal function and/or promote cell transformation. The relative efficiency or dysfunction of the cell death program could therefore have a direct impact on the risk of degenerative or neoplastic disease. Dietary restriction of rodents is a noninvasive intervention that has been reproducibly shown to retard tumor development and most physiologic indices of aging relative to ad libitum-fed animals. As such, it provides a powerful model in which to study common mechanistic processes associated with both aging and cancer. In a recent study we established that chronic dietary restriction (DR) induces an increase in spontaneous apoptotic rate and a decrease in cell proliferation rate in hepatocytes of 12-month-old B6C3F1 DR mice relative to ad libitum (AL)-fed mice. This diet-induced shift in cell death/proliferation rates was associated with a marked reduction in subsequent development of spontaneous hepatoma and a marked increase in disease-free life span in DR relative to AL-fed mice. These results suggest that total caloric intake may modulate the rates of cell death and proliferation in a direction consistent with a cancer-protective effect in DR mice and a cancer-promoting effect in AL mice. To determine whether the increase in spontaneous apoptotic rate was maintained over the life span of DR mice, apoptotic rates were quantified in 12-, 18-, 24- and 30-month-old DR and AL mice. The rate of apoptosis was elevated with age in both diet groups; however, the rate of apoptosis was significantly and consistently higher in DR mice regardless of age. In double-labeling experiments, an age-associated increase in the glutathione S-transferase-II expression in putative preneoplastic hepatocytes in AL mice was rapidly reduced by apoptosis upon initiation of DR. Thus, intervention that promote a low-level increase in apoptotic cell death may be expected to protect genotypic and phenotypic stability with age. If during tumor promotion an adaptive increase in apoptosis effectively balances the dysregulated increase proliferation, the risk of permanent genetic error and carcinogenesis would be minimized.

Aging↗
PubMed1998

U.S. Food and Drug Administration perspective of the inclusion of effects of low-level exposures in safety and risk assessment.

A brief overview is provided of some of the general safety and risk assessment procedures used by the different centers of the U.S. Food and Drug Administration (U.S. FDA) to evaluate low-level exposures. The U.S. FDA protects public health by regulating a wide variety of consumer products including foods, human and animal drugs, biologics, and medical devices under the federal Food, Drug, and Cosmetic Act. The diverse legal and regulatory standards in the act allow for the consideration of benefits for some products (e.g., drugs) but preclude them from others (e.g., food additives). When not precluded by statutory mandates (e.g., Delaney prohibition), the U.S. FDA considers both physiologic adaptive responses and beneficial effects. For the basic safety assessment paradigm as presently used, for example in the premarket approval of food additives, the emphasis is on the identification of adverse effects and no observed adverse effect level(s) (NOAEL). Generally, the NOAEL is divided by safety factors to establish an acceptable exposure level. This safety assessment paradigm does not preclude the consideration of effects whether they are biologically adaptive or beneficial at lower dose levels. The flexibility to consider issues such as mechanisms of action and adaptive and beneficial responses depends on the product under consideration. For carcinogenic contaminants and radiation from medical devices, the U.S. FDA considers the potential cancer risk at low exposure levels. This generally involves downward extrapolation from the observed dose-response range. The consideration of adverse effects of other toxicologic end points (e.g., reproductive, immunologic, neurologic, developmental) associated with low exposure levels is also becoming more of a reality (e.g., endocrine disrupters). The evaluation of the biologic effects of low-level exposures to toxic substances must include whether the effect is adverse or a normal physiologic adaptive response and also determine the resiliency of a physiologic system. The public health mandate of the U.S. FDA includes an active research program at the National Center for Toxicological Research and the other U.S. FDA centers to support the regulatory mission of the U.S. FDA. This includes the development of knowledge bases, predictive strategies, and toxicologic studies to investigate effects at the lower end of the dose-response range. Because of the wide diversity of legal and regulatory standards for various products regulated by the U.S. FDA agency-wide safety and risk assessment procedures and policies generally do not exist.

Animals↗
PubMed1998

Tumors and DNA adducts in mice exposed to benzo[a]pyrene and coal tars: implications for risk assessment.

Current methods to estimate the quantitative cancer risk of complex mixtures of polycyclic aromatic hydrocarbons (PAH) such as coal tar assume that overall potency can be derived from knowledge of the concentration of a few carcinogenic components such as benzo[a]pyrene (B[a]P). Genotoxic damage, such as DNA adducts, is thought to be an essential aspect of PAH-induced tumorigenesis and could be a biomarker for exposure useful for estimating risk. However, the role of B[a]P and the relationship of adduct formation in tumorigenesis have not been tested rigorously in models appropriate for human health risk assessment. Therefore, we directly compared tumor induction and adduct formation by B[a]P and coal tars in several experimental protocols, including one broadly accepted and used by regulators. We found that B[a]P content did not account for tumor incidences after exposure to coal tars. DNA adducts were found in both tumors and tumor-free tissue and tumor outcomes were not predicted by either quantitation of total DNA adducts or by the DNA adduct formed by B[a]P. These data suggest that risk assessments based on B[a]P content may not predict accurately risk to human health posed by environmental PAH.

Administration, Oral↗
PubMed1997

Health risk assessment practices in the U.S. Food and Drug Administration.

The U.S. Food and Drug Administration (FDA) regulates a wide variety of consumer products. Safety issues involve chemical and microbial contaminants in food, biologies, and medical devices; side effects from prescription and nonprescription drugs; residues of animal drugs in food; and radiation from electronic devices. Because of this wide diversity, the legal standards, rules, and policies governing the regulation of these products differ considerably. Hence, risk assessment and risk management practices within the FDA are of necessity quite diverse. This paper presents a summary of risk assessment practices at each of the product centers of the FDA (Center for Food Safety and Applied Nutrition, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, and Center for Veterinary Medicine) and of the development of risk assessment procedures at the National Center for Toxicological Research.

Animals↗
PubMed1997

A carcinogenesis model describing mutational events at the DNA adduct level.

A stochastic carcinogenesis model is proposed to describe a sequence of component mutational changes that constitute the G:C-->A:T base substitution. This paper provides the biological basis and mathematical formulation underlying the proposed model. In addition, the paper elaborates on a numerical approach for studying the cumulant functions, survival functions, and hazard functions of the model. Several numerical examples are given of potential applications of the model.

Base Composition↗
PubMed1996

On interspecies correlations of carcinogenic potencies.

It has been established in the literature that constraints on the designs of experiments used to estimate carcinogenic potencies cause overestimation of true biological interspecies correlations of such potencies. This article explores the potential for appreciable underestimation of interspecies correlations, due to the experimental error that occurs in the estimation of carcinogenic potencies.

Animals↗
PubMed1996

Estimating the probability of occurrence of tumor for a rare cancer with zero occurrence in a sample.

In many physical situations one needs to estimate the probability of occurrence of a rare event based on a random sample when the event has not occurred at all. For example, if the true lifetime incidence of a tumor at a particular tissue site is less than 1%, it is not uncommon to observe no tumors in a typical sample size of 50 animals. This paper explores the suitability of nonzero Bayesian estimation procedures to replace zero maximum likelihood estimates for tissue sites with nonzero background tumor incidences.

Animals↗
PubMed1996

Precision of benchmark dose estimates for continuous (nonquantal) measurements of toxic effects.

The benchmark dose (BMD) corresponding to a low level of the risk of induced disease, e.g., 1 to 10%, has been proposed by various authors as a replacement for the no observed adverse effect level for noncancer endpoints in the regulation of the conditions of exposure to chemicals. This paper focuses on the variability of estimates of the BMD for nonquantal (continuous measurements) of biological endpoints such as are encountered for hematological data, clinical chemistry, and studies of neurotoxic effects. For biological endpoints that can be described by a normal distribution, estimates of the mean and standard deviation are required to calculate the BMD. Estimates of the standard deviation generally are quite variable, particularly for small sample sizes. The purpose of this paper is to examine the precision of the estimates of risk and of the BMD resulting from the inherent variability of the estimates of the standard deviations particularly for bioassays that employ a small number of animals. When the standard deviation is underestimated, the BMD and the regulatory "safe" dose are underestimated. Conversely, when the standard deviation is overestimated, the BMD and safe dose are overestimated. Overestimation of the BMD can be reduced or eliminated by using a lower confidence limit. The worst cases arise where only a few animals are used per dose and the dose response is supralinear (changes rapidly at low doses and levels off at higher doses). If the standard deviation is constant across doses (for lognormally distributed data if the coefficient of variation is constant), a pooled estimate across doses of the standard deviation can be used. In this case, for bioassays employing a total of 40 to 50 animals, the calculation of the BMD will generally be within a factor of 2 of the true value. When the standard deviation is not constant across dose groups, it is desirable to have more than 10 animals per dose group.

Animals↗
PubMed1996

Quantalization of continuous data for benchmark dose estimation.

Benchmark doses corresponding to low levels of noncancer disease risk have been proposed to replace the no-observed-adverse-effect level for establishing allowable daily intakes or reference doses. For quantal data each animal is classified with or without a disease. The proportion of animals with an adverse effect (risk) is observed as a function of dose of a toxic substance. The calculation of a benchmark dose is relatively straightforward. For continuous data a somewhat more complicated designation of risk is required. Because of the more direct procedures with quantal data, consideration could be given to converting continuous data to quantal data before estimating benchmark doses. The purpose of this paper is to compare the precision of the two approaches (use of continuous or quantalized data) for a number of sublinear dose-response curves ranging from low to high probabilities of risk at the highest dose. In these studies, five animals per dose were generally satisfactory to estimate the benchmark dose for continuous data, whereas the corresponding quantalized data generally do not perform as well even with 10 to 20 animals per dose. For quantalized data, the lower 95% confidence limits on the estimates of the benchmark dose were generally a factor of 3 to 4 below the true benchmark dose, whereas the confidence limits using the continuous data were generally within a factor of 2 of the true benchmark dose. Although the use of quantalized data for the estimation of risk is more direct, estimates of benchmark doses using the continuous data were more precise. Based on this study, converting continuous data to quantal data is not recommended.

Animals↗
PubMed1996

Risk assessment of nongenotoxic carcinogens based upon cell proliferation/death rates in rodents.

Increased cell proliferation increases the opportunity for transformations of normal cells to malignant cells via intermediate cells. Nongenotoxic cytotoxic carcinogens that increase cell proliferation rates to replace necrotic cells are likely to have a threshold dose for cytotoxicity below which necrosis and hence, carcinogenesis do not occur. Thus, low dose cancer risk estimates based upon nonthreshold, linear extrapolation are inappropriate for this situation. However, a threshold dose is questionable if a nongenotoxic carcinogen acts via a cell receptor. Also, a nongenotoxic carcinogen that increases the cell proliferation rate, via the cell division rate and/or cell removal rate by apoptosis, by augmenting an existing endogenous mechanism is not likely to have a threshold dose. Whether or not a threshold dose exists for nongenotoxic carcinogens, it is of interest to study the relationship between lifetime tumor incidence and the cell proliferation rate. The Moolgavkar-Venzon-Knudson biologically based stochastic two-stage clonal expansion model is used to describe a carcinogenic process. Because the variability in cell proliferation rates among animals often makes it impossible to detect changes of less than 20% in the rate, it is shown that small changes in the cell proliferation rate, that may be obscured by the background noise in rates, can produce large changes in the lifetime tumor incidence as calculated from the Moolgavkar-Venzon-Knudson model. That is, dose response curves for cell proliferation and tumor incidence do not necessarily mimic each other. This makes the use of no observed effect levels (NOELs) for cell proliferation rates often inadmissible for establishing acceptable daily intakes (ADIs) of nongenotoxic carcinogens. In those cases where low dose linearity is not likely, a potential alternative to a NOEL is a benchmark dose corresponding to a small increase in the cell proliferation rate, e.g., 1%, to which appropriate safety (uncertainty) factors can be applied to arrive at an ADI.

Animals↗
PubMed1996

A simple upper limit for the sum of the risks of the components in a mixture.

Natural or manufactured products may contain mixtures of carcinogens and the human environment certainly contains mixtures of carcinogens. Various authors have shown that the total risk of a mixture can be approximated by the sum of the risks of the individual components under a variety of conditions at low doses. Under these conditions, summing the individual estimated upper bound risks, as currently often done, is too conservative because it is unlikely that all risks for a mixture are at their maximum levels simultaneously. In the absence of synergism, a simple procedure is proposed for estimating a more appropriate upper bound of the additive risks for a mixture of carcinogens. These simple limits also apply to noncancer endpoints when the risks of the components are approximately additive.

Biometry↗
PubMed1996

On the correlation coefficient between the TD50 and the MTD.

The existence of correlation between the carcinogenic potency and the maximum tolerated dose has been the subject of many investigations in recent years. Several attempts have been made to quantify this correlation in different bioassay experiments. By using some distributional assumptions, Krewski et al. derive an analytic expression for the coefficient of correlation between the carcinogenic potency TD50 and the maximum tolerated dose. Here, we discuss the deviation that may result in using their analytical expression. By taking a more general approach we derive an expression for the correlation coefficient which includes the result of Krewski et al. as a special case, and show that their expression may overestimate the correlation in some instances and yet underestimate the correlation in other instances. The proposed method is illustrated by application to a real dataset.

Animals↗
PubMed1995

Risk assessment strategies for neuroprotective agents.

Neurotoxicity may be defined as any adverse effect on the structure or function of the central and/or peripheral nervous system by a biological, chemical, or physical agent. Neurotoxic effects may be permanent or reversible, produced by neuropharmacological or neurodegenerative properties of a neurotoxicant, or the result of direct or indirect actions on the nervous system. A multidisciplinary approach is necessary to assess neurotoxicity because of the complexity and diverse functions of the nervous system. Many of the relevant effects can be measured directly by neurochemical, neurophysiological, and neuropathological techniques, whereas, others must be inferred from observed behavior. Some neurotoxicological data can be derived directly from humans. Neurotoxicity in humans is most commonly measured by relatively noninvasive neurophysiologic and neurobehavioral methods that assess cognitive, affective, sensory, and motor function. For most toxicological assessments, however, it is necessary to rely on information derived from animal models. There are many approaches that can be used to assess neurotoxicity, including whole animal (in vivo) and tissue/cell culture (in vitro) testing. Neurotoxicity can be described at multiple levels of organization, including neurochemical, anatomical, physiological, and behavioral. An important aspect of neurotoxic endpoint evaluation involves risk assessment procedures. Risk assessment may be defined as an empirically-based process used to determine the probability that adverse or abnormal effects are associated with exposure to a chemical, physical or biological agent. Risk management, on the other hand, is the process that applies information obtained through the risk assessment process to determine whether the assessed risk should be reduced and, if so, to what extent. For chemicals such as neuroprotective agents and other drugs designed to provide therapeutic benefits, information concerning these benefits is considered during the risk management phase. The risk assessment process usually involves four steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. Neurotoxicity risk assessment models of the future may well include biomarkers of both effect and exposure as well as biologically-based mechanistic and pharmacokinetic considerations derived from both epidemiologic and experimental data.

Animals↗
PubMed1995

Neurotoxicity modeling for risk assessment.

The setting of acceptable exposure levels for neurotoxicants has followed the traditional approach of dividing experimental no-observed-adverse-effect-levels (NOAELs) by safety/uncertainty factors. NOAELs are believed by many toxicologists to represent levels having zero or negligible risk, while uncertainty factors are used to account for a number of sources of variation. Although the use of NOAELs in this manner has been criticized because of their imprecise quantitative definition, NOAELs for nonquantal neurotoxic effects have not been replaced by more precisely defined quantities (e.g., benchmark doses), partly due to the absence of a generally accepted methodology for attaching specific risk levels to low exposures. The present paper describes a quantitative approach to modeling nonquantal neurotoxic effects for risk assessment, which can be used to obtain results similar to the familiar results obtained in risk assessment for carcinogenicity and developmental toxicity. The steps involved in implementing the process are discussed, with particular attention being given to the critical step of defining an adverse neurologic effect. An experimental data set is used to illustrate the methodology.

Animals↗
PubMed1995

Quick estimate of the regulatory virtually safe dose based on the maximum tolerated dose for rodent bioassays.

With a limited subset of National Cancer Institute/National Toxicology Program (NCI/NTP) bioassays, Gaylor (Regul. Toxicol. Pharmacol. 9, 101-108, 1989) showed that the regulatory virtually safe dose (VSD), corresponding to an estimated lifetime cancer risk of less than 10(-6), could be estimated within a factor of 10 simply by dividing the maximum tolerated dose (MTD), estimated from the results of a 90-day study, by 380,000. The purpose of this current study was to extend the analysis to all carcinogens in the Carcinogenic Potency Database (CPDB) utilizing the TD50 (average daily dose rate in mg/kg body wt/day that was estimated to halve the probability of remaining tumor-free at a specified tissue site throughout a 2-year study). Using the relationship between the upper bound on the low-dose slope (q1*) and the TD50 reported by Krewski et al. (Risk Anal. 13, 383-398, 1993) and the ratio of the maximum dose tested (Max-D)/TD50 obtained in our present analysis, an estimate of the regulatory VSD was given by the MTD/740,000, for NCI/NTP rodent carcinogens. This was about a factor of two lower than the limited analysis conducted by Gaylor. There was little difference when the chemicals were divided into mutagens and nonmutagens. Ninety-six percent (134 of the 139 NCI/NTP rodent carcinogens) of the regulatory VSDs calculated from the individual TD50s obtained from the 2-year bioassays were within a factor of 10 of the MTD/740,000.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗