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Biomedical subjects

D J Benford

Publications and source records attributed to D J Benford.

At least 19 recordsLinked to original sources
PubMed1999

Factors influencing the carcinogenicity of food chemicals.

The relationship between food and cancer is extremely complex. It is generally accepted that diet is a contributory factor in the aetiology of a large proportion of cancers, but with very few exceptions, we are unable to identify specific causal agents. Many food components have genotoxic potential and more are produced endogenously during digestion. Conversely, there is increasing evidence that consumption of some foods may decrease the risk of cancer, and a number of plant constituents have been shown to have the potential to inhibit various stages of the carcinogenic process. Yet we have little understanding of the interactions between the different food-related genotoxic and protective factors. A further complication is the variation in individual susceptibility and vulnerability. As a result we are still not able to determine the optimal diet for minimising cancer risk. In recognition of these issues, the UK Ministry of Agriculture, Fisheries and Food (MAFF) is funding a number of projects aimed at providing greater mechanistic understanding of the links between food and cancer, in order to offer detailed advice to the public. This report summarises the proceedings of a workshop entitled 'Factors influencing the carcinogenicity of food chemicals', held in London on 1 June 1998, providing overviews of some of the key issues, and demonstrating how the MAFF-funded research is contributing to advances in these areas. It includes discussion of genetic polymorphisms and how they may contribute to individual susceptibility and help to identify causal links between food components and colorectal cancer. Biomarkers of DNA damage in human studies and of inhibition of carcinogen activation and endogenous formation of genotoxic reactive nitrogen species are examined. Also considered are the potential uses of physiologically based pharmacokinetic modelling techniques for providing more accurate estimates of risk and reducing the uncertainty in extrapolation between species and doses. Research now in progress will help to establish the critical risk and protective factors involved in diet-related colorectal cancers, in order to provide a sound scientific basis for formulation of dietary advice to the public.

Biomarkers↗
PubMed1999

Dermal route in systemic exposure.

To evaluate risk from dermal exposure, the amount of material on the skin must first be measured. The potential for dermal uptake must then be assessed for the potential health effects from systemic exposure. No standard methods exist for studying these processes, and published data are not comparable because of the different techniques used. Future validated methodology should provide a sound scientific basis for risk assessment. Methods for measuring skin and surface contamination will require development of reference contaminated surfaces and skin as part of quality control procedures. Biological monitoring is a valuable tool in the assessment of dermal absorption, in contributing to the validation of in vitro techniques, and in risk assessment and management. It will be necessary to conduct detailed investigations to support risk assessment for dermal exposure. Ultimately, predictive models will be established for exposure and for dermal absorption to support a generic approach and allow risk assessment strategies appropriate to actual workplace situations.

Environmental Monitoring↗
PubMed1995

Comparison of tumour promoter-induced prostaglandin E2 release in human and rat keratinocytes.

Prostaglandin E2 (PGE2) is associated with phorbol ester-induced skin irritation and tumour promotion, but the mechanism of action is not fully understood and the role of keratinocyte-derived PGE2 is unclear. PGE2 was recently reported to modulate keratinocyte differentiation and phorbol-12-myristate-13-acetate (PMA), the most extensively studied phorbol ester tumour promoter in mouse skin, was shown to stimulate PGE2 release in human keratinocytes. Preliminary data on PGE2 release induced by PMA, mezerein, anthralin, sodium dodecyl sulphate and acetic acid in human keratinocyte cultures is compared to their response in rat keratinocytes. Our data confirms a previously published report on stimulation of PGE2 release by PMA in human keratinocytes and also demonstrates a difference in the magnitude of the PMA- and mezerein-induced response between human and rat keratinocyte cultures at non-cytotoxic concentrations. Cytotoxicity was evaluated by the Neutral Red uptake assay and a concentration that reduced cell viability to 50% of control was selected as a maximum concentration for subsequent measurement of PGE2 release. In contrast, anthralin, sodium dodecyl sulphate and acetic acid induced a similar degree of PGE2 release in human and rat keratinocyte cultures, but release was specifically associated with a cytotoxic response. Non-cytotoxic concentrations of these three chemicals did not stimulate release of PGE2. This study illustrates that PGE2 dose-response curves may reflect different mechanisms of action that may be intimately associated with skin irritant and tumour promoting activity. The data indicates a possible species difference in keratinocyte response to PMA and mezerein. The important value of keratinocyte cultures for mechanistic studies of tumour promotion and skin irritation is highlighted and further research is warranted into the potential role of intracellular pathways, which modulate keratinocyte differentiation and proliferation, in these processes.

Acetates↗
PubMed1994

Investigations of the genotoxicity and cell proliferative activity of dichlorvos in mouse forestomach.

This study investigated the possible mechanism by which dichlorvos may have caused forestomach tumours in mice in a chronic corn oil gavage cancer bioassay [NTP (1989) Toxicology and carcinogenesis studies of dichlorvos in F344/N rats and B6C3F1 mice (gavage studies). National Toxicology Program Technical Report 342, NIH Publ. No 89-2598]. For this purpose, a method has been developed to assess the genotoxicity of irritant substances on mouse forestomach epithelium. Groups of five B6C3F1 mice were given a single oral dose of dichlorvos, the genotoxic forestomach carcinogen 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) or the irritant, non-genotoxic forestomach carcinogen butylated hydroxyanisole (BHA). After periods of 2-48 h, three parameters were assessed: unscheduled DNA synthesis (UDS) by autoradiography of tissue sections, replicative DNA synthesis (RDS) also by autoradiography of incorporated [3H]thymidine, and histopathological changes, including hyperplasia. MNNG induced UDS but not RDS or hyperplasia in forestomach epithelium, consistent with its genotoxic mode of action. BHA and dichlorvos did not induce UDS, consistent with absence of genotoxic activity in the forestomach after in vivo exposure. In contrast, BHA and dichlorvos induced RDS and subsequent hyperplasia, which is likely to result from irritant damage. These data suggest that the chronic effects of dichlorvos on mouse forestomach epithelium in the oral gavage bioassay were mediated via enforced cell proliferation, rather than by a genotoxic mechanism.

Animals↗
PubMed1993

Chemically-induced unscheduled DNA synthesis in cultures of adult human epidermal keratinocytes.

Skin is a major target organ for many experimental carcinogens that exist in our environment and the majority of previous carcinogenicity studies have utilised animal derived models. In view of the fact, that many of these environmental chemicals exhibit species- and tissue-specific metabolism, a human skin tissue derived model would be a distinct advantage. Squamous epithelial carcinoma is a predominant form of skin cancer in man and, in theory, human epidermal keratinocytes present an appropriate target cell to employ as an in vitro system to study epidermal carcinogenesis. This report demonstrates the valuable potential of human keratinocyte cultures as a suitable model for mechanistic studies on factors which may influence DNA damage and, hence, the subsequent development of cancer in human epidermis. Keratinocytes were serially cultivated from adult human skin samples and maintained in culture for at least 3 passages. Tertiary cultures, isolated from 3 separate individuals, were exposed to the direct-acting experimental carcinogen, methyl methanesulphonate (CAS No. 66-27-3), and benzo[a]pyrene (CAS No. 50-32-8), which requires metabolic activation. DNA repair was assessed by a quantitative autoradiographic technique. Methyl methanesulphonate and benzo[a]pyrene both elicited a dose-related increase in unscheduled DNA synthesis in cultures prepared from each individual. Inter-individual variation in the response was observed for each chemical, but this was greater in the case of benzo[a]pyrene, which indicates inter-individual variation in both xenobiotic metabolism activity and DNA repair capacity.

Adult↗
PubMed1991

The application of a wedge perfusion technique to the in vivo-in vitro rat hepatocyte DNA-repair assay.

The in vivo-in vitro rat hepatocyte DNA-repair assay is regarded as labour-intensive and time-consuming to perform. This has tended to impose limitations on its use as a routine procedure for assessing the potential genotoxicity of chemicals. We have developed a simple wedge-perfusion technique which enables hepatocytes to be isolated from several different rats simultaneously. Hepatocyte yield and metabolic capacity are comparable to those isolated by conventional whole-liver perfusion. Hepatocyte viability was generally superior to that obtained when performing multiple in situ perfusions for the rat hepatocyte UDS assay. The median lobe is routinely used but no difference was observed in the UDS response to the positive control genotoxic agents, methyl methanesulphonate (MMS, CAS No. 66-27-3) and 2-acetylaminofluorene (AAF, CAS No. 53-96-3), in hepatocytes isolated from the median or either lateral lobe. The use of Williams medium E or Leibovitz L15 culture medium did not influence the response. This perfusion technique greatly reduces the time, equipment and personnel required and therefore the cost for hepatocyte isolation. It also facilitates the inclusion of concurrent control groups at each time point of assay.

2-Acetylaminofluorene↗
PubMed1990

The short-term effects of carcinogens and sulphur dioxide on the nuclear size of rat nasal epithelial cells.

Enlarged nuclei have been observed frequently as an early carcinogen-induced change in both cultured cells and in target tissues in vivo. The purpose of this work was to examine the occurrence of nuclear enlargement in the upper respiratory tract of rats to provide further evidence of whether nuclear enlargement is a reliable marker of carcinogenesis, and if it could be used as a short-term test for respiratory carcinogens. Carcinogen-induced nuclear enlargement is best demonstrated in vivo when the tissue involved has been undergoing rapid replication. Male Wistar albino rats were simultaneously exposed to an atmosphere containing sulphur dioxide (which caused a hyperplastic response in the nasal cavity) and received an i.p. injection of a nitrosamine. Sections were prepared from the nasal cavity, and the nuclear areas of respiratory epithelial cells were measured. There were some increases in nuclear size 24 and 72 h after the start of treatment. The reversal of this effect 120 h after the start of treatment may have been due to the loss of the normal ciliated mucosal epithelium, and subsequent loss of metabolic capability.

Animals↗
PubMed1988

Metabolizing systems in cell culture cytotoxicity tests.

1. The addition of 9000 g supernatant of rat liver homogenate (S9) or rat liver microsomal fractions to a cytotoxicity test system using BCL-D1 cells has been investigated. 2. The choice of culture medium influenced the intrinsic cytotoxicity of the metabolising system to the BCL-D1 cells. Use of Ham's F10 nutrient mixture resulted in greater cytotoxicity compared with several other media. 3. Microsomal fractions provided greater cytochrome P-450 dependent activation of cyclophosphamide and were less cytotoxic than S9. 4. Direct-acting toxic compounds, such as p-aminophenol, were less toxic in the presence of a metabolising system. This was due to protein-binding rather than enzymic detoxification.

Acrolein↗
PubMed1983

Mechanistic studies on the activation of biphenyl 2-hydroxylation by glucocorticoids.

In order to establish the mechanism by which the selective activation of biphenyl 2-hydroxylation by betamethasone occurs the effect of modifying possible critical factors in the hydroxylation process has been examined. Activation of biphenyl 2-hydroxylation by betamethasone was found in detergent-solubilized rat liver microsomes indicating that intact microsomal membranes are probably not necessary for the activation. Betamethasone had no effect on the spectrally apparent binding of biphenyl or of other type I, type II or reverse type I model substrates. The activation process did not appear to be greatly influenced by changing the ratio of cytochrome P-450 reductase to cytochrome P-450 nor by changing the amount of NADPH. Addition of NADH increased the extent of activation suggesting that betamethasone facilitates transference of the second electron to cytochrome P-450. However, betamethasone also stimulated cumene hydroperoxide supported biphenyl 2-hydroxylation; therefore a step subsequent to cytochrome P-450 reduction is also involved in the activation. Activation did not correlate with increased uncoupling of an active oxygen-cytochrome P-450 complex to form hydrogen peroxide.

Animals↗
PubMed1983

Tissue and sex differences in the activation of aromatic hydrocarbon hydroxylases in rats.

Betamethasone and alpha-naphthoflavone produced similar activation of biphenyl 2-hydroxylase and benzo[a]pyrene 3-hydroxylase in control male rat liver microsomes. In small intestinal epithelial microsomes, betamethasone had no effect whereas alpha-naphthoflavone caused a pronounced activation of benzo[a]pyrene hydroxylation and a lesser activation of biphenyl 2-hydroxylation. In lung microsomes, betamethasone had no effect on either enzyme activity whereas alpha-naphthoflavone had no effect on biphenyl 2-hydroxylase but inhibited benzo[a]pyrene hydroxylase. In kidney cortex microsomes from male rats both compounds caused inhibition or had no effect whereas in kidney cortex microsomes female rats betamethasone activated whereas alpha-naphthoflavone had no effect. Activation also occurred in isolated viable hepatocytes from male rats. The response of biphenyl 2-hydroxylase was very similar to that found in male rat liver microsomes but benzo[a]pyrene hydroxylase was more sensitive to activation and less sensitive to inhibition than in microsomes. The findings are interpreted as demonstrating the presence of more than one 'latent' aromatic hydrocarbon hydroxylase in rodents.

Animals↗
PubMed1980

Activation of hepatic microsomal biphenyl 2-hydroxylation by corticosteroids.

1. 4-Hydroxylation was a major route of biphenyl metabolism in liver microsomes from control and phenobarbitone-pretreated rats, with 2- and 3-hydroxybiphenyl as lesser metabolites. 2. Many corticosteroids, when added to the microsomal incubation mixture, selectively increased 2-hydroxylation with little or no effect on 3- and 4-hydroxylation. Betamethasone caused the greatest activation (400%). 3. In liver microsomes from controls hamsters and 3-methylcholanthrene-pretreated rats, the basal hydroxylase activity, especially 2-hydroxylation, was much higher, but the quantitative increase following betamethasone addition was similar to that in liver microsomes from control and phenobarbitone-pretreated rats. 4. Pretreatment of rats with betamethasone also resulted in a small increase in biphenyl 2-hydroxylation activity after 4 h, returning to control values after 6 h. 5. In vitro addition of estradiol or testosterone had no effect on either basal or betamethasone-activated biphenyl 2-hydroxylation.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Irritancy testing in cultured keratinocytes.

A differentiating keratinocyte cell line derived from explant cultures of rat sublingual epithelium has been used as a potential in vitro model for topical (skin) irritation of a range of detergents. The end points used to assess toxicity were acid phosphatase (AP) activity after 4 h of dosing and neutral red (NR) uptake and kenacid blue (KB) staining after 3 d to assess cell viability and number. The acid phosphatase activity increased to a sharp peak with increasing doses, then fell equally sharply for the anionic detergent sodium dodecyl sulfate (SDS) and cationic detergents TMABs (trimethylammonium bromides). With the Tweens (the least toxic group) there was no acid phosphatase peak or it appeared at the highest dose level used (1.0 mg/ml). The dose-response curves for NR uptake paralleled those for KB staining. With all of the three end points, it was apparent that the order of toxicity for the different groups was TMABs greater than SDS greater than Tweens, with a difference of one order of magnitude between consecutive groups when using NR and KB.

Acid Phosphatase↗