Biomedical subjects

G M Williams

Publications and source records attributed to G M Williams.

At least 145 records · Page 8Linked to original sources

PubMed1996

Formaldehyde mechanistic data and risk assessment: endogenous protection from DNA adduct formation.

Exposures of rodents to airborne formaldehyde (FA) produce dose-related toxicity, enhanced cell proliferation and squamous cell carcinomas in the nasal passages. The mechanism of FA-induced tumor formation involves DNA-protein crosslink formation and enhanced cell proliferation secondarily to cytotoxicity. The mucociliary apparatus and glutathione protect against low-dose FA-induced effects. Consequently, the mechanistic information is consistent with a very sublinear dose-response curve for tumor formation. The sublinear dose-response of nasal DNA-protein crosslinks levels in rodents and monkeys has been used in the risk assessment of FA.

Animals↗

PubMed1996

N-nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation.

N-Nitrosodiethylamine (NDEA) is DNA reactive after bioactivation and produces tumors in every animal species tested. Bioactivation is effected by several P450 isozymes including CYP2E1, which is ethanol inducible. Tumor formation in rat liver was proportional to O4-ethyldeoxythymidine formation in DNA, which was generally proportional to NDEA dose. At low doses in the 0.033-1.1 ppm range, the dose-response for esophageal tumor formation was sublinear, possibly due to DNA repair. Although no epidemiological studies have specifically evaluated NDEA, sufficient exposure levels would be expected to cause cancer in humans.

Animals↗

PubMed1996

2-Acetylaminofluorene mechanistic data and risk assessment: DNA reactivity, enhanced cell proliferation and tumor initiation.

The aromatic amine 2-acetylaminofluorene (AAF) produced neoplasms in diverse target organs of many animal species. AAF was DNA-reactive after N-hydroxylation by CYP1A2 in the liver and nitrenium ion formation at the target site. In mouse bladder, AAF-DNA adducts were proportional to dose. An epigenetic component for tumor formation was also present since tumor incidence and hyperplasia showed a threshold dose and decreased following discontinuation of AAF exposure. In contrast, both adduct and tumor formation in the liver were proportional to dose, and discontinuation of AAF did not reduce tumor incidence.

2-Acetylaminofluorene↗

PubMed1996

Benzidine mechanistic data and risk assessment: species- and organ-specific metabolic activation.

The aromatic amine benzidine (BZ) has produced various tumors, including liver tumors, in mice, rats and hamsters. BZ forms DNA adducts in rodent liver, and it is positive in most genotoxicity tests. Only bladder tumors are produced in dogs and in humans who have been occupationally exposed, possibly related to the slow rate of liver detoxification by acetylation, allowing activation of BZ or its metabolites in urine. Despite these differences, risk assessment for humans, based on liver tumors in mice, was approximately predictive of the incidence of bladder tumors observed in industrially exposed humans.

Animals↗

PubMed1996

d-limonene mechanistic data and risk assessment: absolute species-specific cytotoxicity, enhanced cell proliferation, and tumor promotion.

d-Limonene produces tumors only in the kidneys of male rats in association with hyaline-droplet nephropathy, which is due to the accumulation of the rat-specific, low molecular weight protein alpha(2u)-globulin in the P2 segment cells of renal proximal tubules. Human urine contains no alpha(2u)-globulin and, compared with the male rat, much less protein and almost no low molecular weight protein. Genotoxicity tests for d-limonene are negative, and the mechanism of tumorigenesis involves tumor promotion and enhanced cell proliferation. There is no risk of cancer for humans from d-limonene, since the binding of d-limonene to alpha(2u)-globulin would not occur.

Animals↗

PubMed1996

Butylated hydroxyanisole mechanistic data and risk assessment: conditional species-specific cytotoxicity, enhanced cell proliferation, and tumor promotion.

Butylated hydroxyanisole (BHA), at high doses, has been found to induce forestomach squamous cell carcinomas in rodents, but not glandular cell or other types of neoplasms. BHA is not DNA-reactive, and the epigenetic mechanism of tumor formation involves cytotoxicity and enhanced cell proliferation, which are mostly reversible. Humans lack a forestomach and, therefore, are predicted to be much less sensitive than rodents to the effects of BHA. Also, the exposures to humans are well below doses producing the epigenetic effects in rodents. It has been concluded that BHA is an agent whose rodent carcinogenicity is conditionally species-specific and not relevant to humans.

Animals↗

PubMed1996

Phenobarbital mechanistic data and risk assessment: enzyme induction, enhanced cell proliferation, and tumor promotion.

Chronic exposure to high doses of phenobarbital (PB) causes hepatocellular adenomas in both mice and rats and hepatocellular carcinomas in some strains of mice. Long-term PB therapy has not been found to cause human tumors. PB is not DNA reactive, and most genotoxicity tests have yielded negative results. PB has been extensively studied as an epigenetic, rodent liver tumor promoter. At exposures causing rodent liver tumors, PB has measurable effects on hepatocytes: PB inhibits cell-to-cell communication; PB induces enzymes, including P450 cytochromes; PB stimulates proliferation and inhibits apoptosis of hepatocytes in neoplastic foci. Threshold exposures for some of these endpoints coincide with the threshold exposure for tumorigenesis.

Animals↗

PubMed1996

2,3,7,8-Tetrachlorodibenzo-p-dioxin mechanistic data and risk assessment: gene regulation, cytotoxicity, enhanced cell proliferation, and tumor promotion.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been found to cause several tumor types in rodents, but TCDD has not been proven to cause cancer in humans, although there have been reported associations. TCDD does not bind to DNA, and indirect tests for DNA damage have been mostly negative. Tumorigenicity by TCDD in rodents has been linked to cellular necrosis, enhanced cell proliferation and tumor promotion. TCDD binds to the Ah receptor, which induces CYP1A1. This binding may be involved in tumorigenicity in rodents; however, additional TCDD-induced toxic changes appear to be required. Biopersistence and organ distribution may play an important role in TCDD dosage extrapolation to humans, but these have not been adequately determined.

Animals↗

PubMed1996

Saccharin mechanistic data and risk assessment: urine composition, enhanced cell proliferation, and tumor promotion.

Sodium saccharin (NaSac) produces bladder tumors consistently in male rats only after lifetime exposure that begins at birth. NaSac is not metabolized and is negative in most genotoxicity tests. NaSac-induced cell damage and proliferation have been proposed as important factors in tumor promotion, and dose-response information demonstrating a threshold for these parameters is available. One theory proposes that high levels of NaSac, combined with protein in a high Na+, high pH environment found only in the male rat, form toxic microscopic crystals; therefore, NaSac-induced tumors may not be relevant to human carcinogenesis.

Animals↗

PubMed1996

Genotoxicity and subchronic toxicity studies with heated olestra.

Olestra is a class of sucrose-fatty acid polyesters intended for use as a non-caloric replacement of edible oil. Genotoxicity and subchronic toxicity studies were conducted to determine whether olestra could form genotoxic or toxic breakdown products during simulated commercial use. Heated olestra was prepared for these studies by batch-frying potato slices in olestra at 177-185 degrees C for 25-32 hr over 5-7 days. Genotoxicity of this previously heated olestra was assessed in four standard in vitro assays: (1) Salmonella mutagenesis (Ames test); (2) forward mutagenesis of mouse lymphoma cells at the thymidine kinase locus; (3) unscheduled DNA synthesis in rat hepatocytes; and (4) clastogenicity in cultured Chinese hamster ovary cells. These tests were conducted with previously heated olestra at concentrations up to at least 5 mg/ml both in the absence of exogenous bioactivation and, for assays (1), (2) and (4) with added liver microsomal (S-9) activation. The Ames and mouse lymphoma assays were performed with olestra (10 mg/ml and 23 mg/litre, respectively) either alone or emulsified with the non-toxic, non-ionic surfactant Pluronics F68, both in the presence and absence of metabolic activation. To test for clastogenicity in vivo, rats were administered previously heated olestra by gavage at 5 g/kg per day for up to 5 days and bone marrow cells were examined for chromosomal aberrations. Heated olestra lacked genotoxic activity detectable by the aforementioned assays. Heated olestra was fed to Fischer 344 rats at up to 10% of the diet (w/w) for 91 days. Evaluation of survival, food consumption, feed efficiency, physical condition, body weight, organ weight, haematological and clinical chemistry parameters, and histomorphology revealed no adverse effects attributable to ingestion of heated olestra at exposure levels in excess of those anticipated for human consumption. It is concluded that olestra used as a deep-frying medium conveys no genotoxic or toxic hazard at anticipated levels of human consumption.

Animals↗

PubMed1996

Does donor iliac artery percutaneous transluminal angioplasty or stent placement influence the results of femorofemoral bypass? Analysis of 70 consecutive cases with long-term follow-up.

PURPOSE: Femorofemoral bypass procedures are being performed with increasing frequency in some patients with bilateral disease in whom the "donor" iliac artery undergoes percutaneous transluminal angioplasty or stent placement. This study was undertaken to critically examine the efficacy of this approach. METHODS: The records of 70 consecutive patients who over a 14-year period underwent elective femorofemoral bypass procedures for chronic occlusive disease, including those who did (group I; n = 26) and did not (group II; n = 44) undergo donor iliac percutaneous transluminal angioplasty or stent placement, were reviewed. RESULTS: No significant differences were found between group I and II patients with respect to age, gender, risk factors, surgical indications, preoperative ankle-arm indices, and the performance of associated procedures. One patient (1.4%) died of a myocardial infarction; no other major cardiopulmonary complications occurred. The postoperative change in the group I donor limb ankle-brachial index ranged from -0.18 to 0.11 (mean, 0.00), revealing no significant steal. The primary graft patency rates for group I and II patients 30 days after surgery were 92% and 98%, respectively, and at 1, 3, 5, and 7 years after surgery were 87% and 81%, 79% and 73%, 79% and 59%, and 66% and 59%. CONCLUSIONS: Donor iliac artery percutaneous transluminal angioplasty or stent placement does not compromise the results of femorofemoral bypass procedures in patients with chronic iliac artery occlusive disease.

Adult↗

PubMed1996

Chemical carcinogen mechanisms of action and implications for testing methodology.

Chemical carcinogens are of two distinct types, DNA-reactive and epigenetic. Testing methodology can be directed toward detecting effects of both types of carcinogen. Carcinogens of the DNA-reactive type are defined by the formation of covalently bound DNA adducts. These chemicals have structures that yield electrophilic reactants either directly or after bioactivation. These agents cause genomic alteration in the structure or function of DNA in the target cell. In addition, these compounds can exert other cellular and tissue epigenetic effects, such as cell proliferation and growth promotion. Carcinogens of the epigenetic (paragenetic) type, in contrast, do not react with DNA, but rather display cellular effects such as neoplasm growth promotion, cytotoxicity, inhibition of tissue growth regulation, peroxisome proliferation, endocrine modification, immunosuppression and/or sustained tissue ischemia that can be the basis for increases in neoplasia. Their chemical structure is such that they do not give rise to a reactive electrophile. The testing methodologies to identify either type follow a Decision Point Approach designed to identify potential carcinogenicity and yield mechanistic information on the production of effects that underlie carcinogenicity. It has 5 stages focusing on the chemical structure, DNA-reactivity, epigenetic effects, limited bioassays and finally the application of the accelerated bioassay (ABA). ABA requires 40 weeks and applies the use of sensitive markers for induction of neoplasia in comparison to positive control compounds for important organs in human carcinogenesis. It enables data acquisition of the entire carcinogenic process directed toward developing mechanistic information. The ABA has the potential to replace the chronic bioassay in rodents in some circumstances and can serve as an alternative to a chronic bioassay in a second species.

Animals↗

PubMed1996

Proliferation markers.

Types of growth include embryonic, fetal, neonatal, juvenile and mature. Until full differentiation is achieved, cells grow through proliferation from progenitor cells. At maturity, the cellular genome is fixed with committed patterns of cell cycle duration and adaptation, ranging from static to renewing type 3. The static cell type cannot proliferate and adapts through hypertrophy. The renewing type continuously proliferates even without stimulus. In all cell types the processes of differentiation and proliferation are mutually exclusive. Cellular kinetics involve (a) the duration of the cell cycle, (b) the birth rate of cells, and (c) the growth rate fractions. The duration of the cell cycle is 2-4 days. All growth factors (GF) exert their influence during G1 phase. Release a GF by one cell type can influence the proliferation of another (= paracrine stimulation). At the end of G1 is the point of highest sensitivity to toxicity. Tumor suppressor genes act here through tyrosine phosphorylation. During S, the cell replicates its chromosomes. During G2 the immune surveillance and DNA damage repair mechanisms operate. Injured cells stay here longer enabling repair of their damaged DNA. Cell division involves both nuclear (mitosis) and cytoplasmic (cytokinesis) phases giving rise to 2 new cells. The cell cycle has 2 checkpoints. The first involves the G1-S transition and the second the G2-M transition. The types of cell cycle inhibition include (a) cycle- and phase-specific inhibition; (b) cycle-and nonphase-specific inhibition; (c) noncycle-and nonphase-specific inhibition, and finally (d) noncycle, nonphase-, and nonorgan-specific inhibition. Proliferation is a circadian process and it is stimulated by a variety of stimuli which include (1) interference with hormonal feedback pathways; (2) inhibition of the tissue trophic activity; (3) sustained presence of antigenic substances; (4) tissue ischemia; (5) changes of conditions luminally or on surfaces of tissues; (6) sustained cytotoxicity; (7) cell death; and (8) surgical resection. Proliferation can be arrested through senescence, apoptosis, injury or even during the development of immune cells. In the past, tissue/cell kinetics have been studied by tritiated thymidine histoautoradiography. Recently, monoclonal antibodies to proliferation-associated antigens, have been successfully employed. These antigens are cycle-associated proteins and include (1) PCNA; (2) p53; (3) Ki67; (4) AGNOR; (5) Statin; and (6) BrdU. Practical examples are given comparing PCNA and BrdU markers from 3 tissues, i.e. liver, glandular stomach, and uterus, across 2 or 3 strains of rats. Mean values of labeling indices are cited. Within the PCNA marker, 2 different clones are compared from the glandular stomach of SD rats of 2 different ages. Gender and across species comparisons are also made. All these comparisons denote that in every study where markers are used (a) there is a need for a concurrent study control group of the same age; (b) there is a need for in-house control data for this particular organ by species, strain, gender and age; (c) there is ancillary assessment of the trophic status of the target tissue; (d) there is a need for at least 2 different time points during assessment; (e) there is a need for such proliferation data prior to commencing the 2 year rodent bioassay; and (f) that PCNA is the most reliable and versatile of all markers used, capable of rendering good results even from archival specimens.

Animals↗

PubMed1996

Epigenetic carcinogens: evaluation and risk assessment.

Regulatory policies in the U.S. have been developed based upon a single model of cancer causation, which assumes chemical-induced genetic alterations. Such a model predicts some degree of cancer risk even at extremely low exposure levels. Many chemicals that produce tumors in experimental animals have been shown to act by epigenetic mechanisms that do not involve an attack by the chemical on DNA leading to subsequent genetic alteration. Such indirect mechanisms require prolonged exposures to high levels of chemicals for the production of tumors. For chemicals that are carcinogenic in this manner, the cancer mechanism would not be operative at exposures below a threshold at which the relevant cellular effect does not occur. Also, in contrast to DNA-reactive mechanisms, epigenetic effects may be unique to the rodent species used for testing. Certain chemical tumorigens have been well studied and provide examples for the use of mechanistic information in risk assessment. Butylated hydroxyanisole and saccharin are nongenotoxic food additives for which no risk to humans is predicted based upon low exposure levels and the likelihood that humans are either insensitive or much less sensitive to the tumorigenic effects found in rodent test species. For another non-genotoxic food additive d-limonene, the mechanism that underlies kidney tumor development in male rats is not expected to be operative in humans at all. The pharmaceutical phenobarbital represents a large group of non-genotoxic liver microsome enzyme inducers, which produce liver cancer in mice at levels that are near to therapeutic doses in humans. Epidemiology studies have not shown phenobarbital-related tumors in humans, indicating that humans may be less sensitive to the effects of phenobarbital. The mechanistic considerations involved in the risk assessment of these agents demonstrate that humans are not at risk from current exposure levels of many epigenetic carcinogens.

Animals↗

PubMed1996

Risk assessment of carcinogens in food with special consideration of non-genotoxic carcinogens. Scientific arguments for use of risk assessment and for changing the Delaney Clause specifically.

The document "Risk Assessment of Carcinogens in Food with Special Consideration of Non-Genotoxic Carcinogens" was produced by the International Federation of Societies of Toxicologic Pathologists on the occasion of its triannual meeting in Tours, France, April 23-26, 1995. Subsequently, it was endorsed by the North American Society of Toxicologic Pathologists at its annual meeting in San Diego, CA, USA, June 11-15, 1995. This document was written to address up-to-date risk assessment of carcinogens and anachronisms in the Delaney Clause of the US Federal Food, Drug and Cosmetic Act which have become evident since its enactment in 1958. In the intervening years, major progress has been made in understanding mechanisms of cancer induction and in recognizing causes of human cancer. The Clause in conjunction with its present legal interpretation and implementation does not provide for rational, scientific evaluation of carcinogens. It ignores the fact that the diverse mechanisms now known to underlie cancer increases in rodents exposed to high doses of chemicals are often inapplicable to man. In this regard, current evaluation of chemicals based on the tenets of the Delaney Clause is irrational in many cases. The document presents several examples of chemicals to which humans may be exposed through food and which illustrate the need for science-based risk assessment. Appropriate risk assessment methods are available to provide assurance of negligible risk, and accordingly, it is recommended that the Delaney Clause be rescinded as it has outlived its usefulness. This will enable US governmental agencies to regulate the use of chemicals in foods by using appropriate current scientific methods on a case by case basis within the context of other relevant legislation.

Animals↗

PubMed1996

Diethylnitrosamine exposure-responses for DNA damage, centrilobular cytotoxicity, cell proliferation and carcinogenesis in rat liver exhibit some non-linearities.

The exposure-responses for several effects of limited exposures to diethylnitrosamine (DEN) in the livers of male Fischer 344 rats were measured and phenobarbital promotion was used to enhance expression of initiation of carcinogenesis. Five doses ranging from a cumulative total of 0.5 to 4 mmol DEN per kg body weight were given as weekly i.p. injections for 10 weeks. This was followed by 4 weeks recovery, after which the groups were maintained on either a basal diet or 0.05% phenobarbital (PB) to promote liver tumor development. All doses of DEN produced ethylation in liver DNA, which increased with dose. Indicative of toxicity, the centrilobular zone of glutamine synthetase-positive hepatocytes was reduced in relationship to exposure up to a cumulative exposure of 3 mmol/kg. The two lower exposures to DEN produced no increase in cell proliferation, whereas higher exposures resulted in marked increases, approximately 4-fold between 1.0 and 2.0 mmol/kg cumulative. At the end of the recovery period (14 weeks), hepatocellular altered foci (HAF), which expressed the placental form of glutathione S-transferase, were induced by all exposures, with an increase of approximately 4-fold between the exposures of 1.0 and 2.0 mmol/kg being the greatest. In rats maintained on basal diet or PB for 24 weeks after exposure, HAF increased further and with exposures of 2.0 mmol/kg and above, all rats developed hepatocellular carcinomas. With 1.0 mmol/kg, no liver tumor occurred in 12 rats without promotion, whereas in those given PB, two adenomas and two carcinomas were present in 12 rats. At the lowest exposure of 0.5 mmol/ kg, no tumor occurred in rats on basal diet, although HAF increased approximately 7-fold. With PB promotion, only one adenoma developed in 12 rats and HAF increased another 2-fold. Thus, the findings document non-linearity for some of the effects of DEN and a near no-effect level for initiation of promotable liver neoplasms at the lowest exposure in spite of a substantial induction of HAF.

Alkylating Agents↗

PubMed1996

Strain- and sex-specific variations in hepatic glutamine synthetase activity and distribution in rats and mice.

The distribution of glutamine synthetase (GS) in a mammalian liver is restricted to a small zone of hepatocytes surrounding the central veins. The determination of the size of the GS+ zone in rats by immunohistochemistry revealed that it differed between rat strains and was larger in males than in females of each strain. Accordingly, the means of the relative mean width (RMW) values that characterize the size of the GS+ zone were 19%, 26%, and 39% lower in females than in males of Sprague-Dawley, Wistar, and Fischer rats, respectively. Upon orchidectomy of male rats, the size of the GS+ zone diminished towards the value found in females, while ovariectomy was without effect. This orchidectomy-induced reduction was reflected in corresponding changes of the RMW values as well as in the number of GS+ cells per pericentral field and was not due to the slightly smaller size of the GS+ hepatocytes in the orchidectomized males. No such sex difference was found in M775 mice. Biochemical GS activity was higher in the male rats than in the female rats and changed correspondingly to the distribution after gonadectomy. In the mice, only the specific activity of GS dropped after orchidectomy. In primary cultures of rat hepatocytes, no influence of testosterone or estrogen on GS activity and cellular distribution was observed, even after stimulation of GS activity with dexamethasone and growth hormone. Both sex hormones, however, were able to affect the activity of glucose-6-phosphate dehydrogenase (G6PD). The observed sex differences in the activity and distribution of GS in rat livers suggest that sex hormones not only modulate the level of this enzyme but are at least partially involved in the determination of the size of the compartment of GS expression. According to the results in the cell cultures, the effects of the sex hormones appear indirect rather than direct.

Animals↗

PubMed1996

8-Oxodeoxyguanosine formation in the DNA of cultured cells after exposure to H2O2 alone or with UVB or UVA irradiation.

The objective of the present study was to establish whether H2O2 alone or in the presence of UVA or UVB would give rise to formation of the oxidatively damaged DNA base 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) in cultured adult rat liver (ARL-18) epithelial cells. Hydrogen peroxide alone at 5 mM increased 8-oxo-dG levels by 42% of that of culture control. Compared to culture control, UVB exposure at a dose of 0.63 J/cm2 elevated 8-oxo-dG levels only 8.4%. In the presence of 5 mM H2O2 + UVB (0.63 J/cm2), 8-oxo-dG levels were elevated 155% above culture control suggesting a synergistic effect. A UVA dose of 10 J/cm2 did not elevate 8-oxo-dG levels above culture control. In the presence of 5 mM H2O2 plus UVA (12 J/cm2), 8-oxo-dG levels were elevated 310% above controls compared with an increase of 75.8% above control levels at the same dose in the absence of H2O2. These results reveal that both UVA or UVB can promote H2O2 generation of reactive oxygen species (ROS) in whole cells resulting in an increase in the formation of 8-oxo-dG, although the photodynamic generation of ROS from H2O2 occurs with a much higher efficiency in the presence of UVB. Our study also demonstrates that 8-oxo-dG can be generated in cellular DNA of whole cells exposed to H2O2 and UVA or UVB, indicating that the ROS generated in whole cell systems are long enough lived to migrate to the nucleus and cause DNA damage.

8-Hydroxy-2'-Deoxyguanosine↗