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Biomedical subjects

I F Purchase

Publications and source records attributed to I F Purchase.

At least 37 records · Page 2Linked to original sources
PubMed1987

Vinyl chloride: an assessment of the risk of occupational exposure.

There is little doubt that exposure to high levels of VCM as a consequence of occupation can result in an increased incidence of ASL. A review of 20 epidemiological studies involving about 45,000 workers occupationally exposed to VCM showed that neoplasms of the liver showed an increase in incidence in the majority of studies. For brain cancer the association between exposure to VCM and an increased incidence was less clear because of the lower relative risk. Neoplasms of the respiratory tract, digestive system, lymphatic and haemopoietic system, buccal cavity, and pharynx, cardiovascular system and colon/stomach were reported to show an increased incidence in one or more studies, but to show no increase, or in some cases a decrease, in incidence in other studies. In view of the increased incidence of breast neoplasms in rodents exposed to VCM, the studies of Chaizze et al. (1980), who did not confirm these findings in humans, are of importance. The register of ASL cases now contains records of 99 persons with confirmed ASL and occupational exposure to VCM. The average latent period between first exposure to VCM and death from ASL is 21.9 years. The majority of cases occurred in autoclave workers, who are recognized as having been exposed to extremely high levels. Although precise estimates of exposure are not available for the periods of most interest, the pattern of cases roughly suggests that extremely high exposures were necessary for the induction of ASL. For example, ASL cases tended to occur in larger numbers in some plants than in others, a finding that can be explained most easily by differences in exposure patterns. There is an extensive series of animal studies on the carcinogenicity of VCM. Some of these precede the epidemiological studies confirming the association between VCM exposure and ASL in man. ASL and neoplasms of a number of other organs have been induced in laboratory rodents by VCM. Estimation of the exposure levels likely to cause a lifetime risk of ASL of 10(-6) on the basis of these data give extremely low levels (down to 3.9 X 10(-7) ppb) which appear to be unrealistic estimates for man. Part of the reason for this is that laboratory studies have shown that VCM is metabolized in the liver (and elsewhere in the body) to the reactive metabolites chloroethylene oxide and chloroacetaldehyde. The rate of conversion is limited at high levels of exposure giving inaccurate estimates of the slope of the dose-response relationship.(ABSTRACT TRUNCATED AT 400 WORDS)

Air Pollutants, Occupational↗
PubMed1987

A balanced approach to the detection, characterisation and mechanism of the toxicity of industrial chemicals.

Several thousands of new chemical entities are synthesised each year in the laboratories of the world. Currently there are estimated to be some 100,000 substances used commercially of the 7 million chemicals recorded by chemical abstracts (Ca 1.5%). Public attention is mainly attracted to the potential life threatening and ill health effects of chemicals such as systemic poisoning, carcinogenicity, teratogenicity and mutagenicity, although there are relatively few proven human chemical carcinogens, teratogens or mutagens. Many substances have been examined in animal toxicity studies for their acute toxic effects, far fewer for chronic toxic effects. The public's perception is that chemicals are toxic. In our laboratory, minimal to no lethal toxic effects were recorded for more than 60% of substances examined at doses below 2000 mg/kg/bwt by either oral or dermal routes. A similar spectrum of chemicals did not elicit skin or ocular irritant or skin sensitisation response in 70-80% of studies. Perversely although toxicity studies reasonably predict the probable human response following exposure, they are a focus of a strong public lobby supported by many scientists to curtail studies in experimental animals. Consequently, much effort is devoted towards the development of "alternative" in vitro and ex-vivo procedures. Often these are empirically based without consideration of the underlying fundamental physiology, biochemistry or toxic mechanism of action. Consequently there can be an over-estimation or expectation of their ability to predict potential toxicity. Attention is seldom directed towards the design requirements of the validation studies needed to test, performance and reproducibility and the evaluation of the parameters of sensitivity and specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Significance of the genotoxic activities observed in vitro for 35 of 70 NTP noncarcinogens.

A speculative analysis is presented of the in vitro genotoxicity data reported by Shelby and Stasiewicz for 70 chemicals defined as noncarcinogenic to rodents by the National Toxicology Program. It is concluded that the genotoxic activities observed are probably subject to logical explanation. It is suggested that short-term genotoxicity assays conducted in vivo on newly defined in vitro genotoxins may have a useful role to play in discriminating animal carcinogens from noncarcinogens. It is clear from the results reported that genotoxic activities observed in vitro for a new test chemical only provide evidence of its possible animal carcinogenicity; they are not definitive of carcinogenicity--the difference may be negligible in general but might prove unacceptable in the particular.

Animals↗
PubMed1985

Hepatocellular carcinoma and dietary aflatoxin in Mozambique and Transkei.

Estimations of the incidence of hepatocellular carcinoma (HCC) for the period 1968-74 in the Province of Inhambane, Mozambique, have been calculated and together with rates observed in South Africa among mineworkers from the same Province indicate very high levels of incidence in certain districts of Inhambane. Exceptionally high incidence levels in adolescents and young adults are not sustained at older ages and suggest the existence of a subgroup of highly susceptible individuals. A sharp decline in incidence occurred during the period of study. Concurrently with the studies of incidence, 2183 samples of prepared food were randomly collected from 6 districts of Inhambane as well as from Manhica-Magude, a region of lower HCC incidence to the south. A further 623 samples were taken during 1976-77 in Transkei, much further south, where an even lower incidence had been recorded. The mean aflatoxin dietary intake values for the regions studied were significantly related to HCC rates. Furthermore, data on aflatoxin B1 contamination of prepared food from 5 different countries showed overall a highly significant relationship with crude HCC rates. In view of the evidence that chronic hepatitis B virus (HBV) infection may be a prerequisite for the development of virtually all cases of HCC and given the merely moderate prevalence of carrier status that has been observed in some high incidence regions, it is likely that an interaction between HBV and aflatoxin is responsible for the exceptionally high rates evident in parts of Africa and Asia. Various indications from Mozambique suggest that aflatoxin may have a late stage effect on the development of HCC. This points to avenues for intervention that could be more rapidly implemented than with vaccination alone.

Adolescent↗
PubMed1984

Genotoxicity and carcinogenicity of fluorocarbons: assessment by short-term in vitro tests and chronic exposure in rats.

Two short-term in vitro tests for mutagenicity (Salmonella reverse mutation and BHK21 cell transformation) were conducted on a series of fluorocarbons. Some of these materials (FC22, FC31, FC142b, FC143, and FC143a) were found to be positive in one or both of the tests and could therefore be considered as being potentially carcinogenic to animals. Such activity was not anticipated for what were previously considered inert materials and in consequence several examples of these fluorocarbons, which represented different combinations of short-term test results, were tested for carcinogenicity in limited in vivo bioassays. In these studies, rats were dosed for 1 year by gavage 5 days a week with either FC22, FC31, FC133a, FC134a, or FC143a dissolved in a corn-oil at a single dosage of 300 mg/kg body weight. The animals were then observed until week 125 with detailed necropsy at termination. The study revealed that FC31 was a potent carcinogen (to the rat stomach), a result which reflected the short-term test predictions, but FC133a, which gave a negative response in both the in vitro assays, induced a high incidence of reproductive tract tumors. The weak bacterial mutagens FC22 and FC143a did not induce tumors in this study, and the nonmutagenic FC134a was without overt carcinogenic activity. It is concluded that, while recognizing the limitations of the in vivo component of this study, the short-term tests were only partially successful in identifying potential carcinogens for this series of chemicals. Fluorocarbon 31 was a potent carcinogen which was first identified by bacterial mutation and cell transformation, whereas the equally potent carcinogen FC133a was not so identified. The lack of genotoxic activity with this particular compound leads us to believe that the carcinogenic activity may be due to mechanisms other than those which involve direct DNA interactions.

Animals↗
PubMed1984

The future of animals in research and teaching. The European scene.

There is an active debate in Europe about the issue of how best to achieve the advances in biology, medicine, and safety assessment which rely on the use of experimental animals, while at the same time providing adequate safeguards for the animals and guidance for those involved in the experiments. On the one hand, public opinion suggests that society is striving toward higher standards of safety and health, while on the other, there is a movement (sometimes vociferous and violent) to reduce or abolish the use of animals for experimental purposes. Against this background the current National and European Economic Community legislation is reviewed, revealing that all countries have some form of legislation currently in force, which demands the testing of chemicals and also which restricts and controls the use of animals. The 21 member countries of the Council of Europe are about to ratify a Convention on the Use of Vertebrate Animals for Experimental Purposes. This convention will form the basis for changes in legislation anticipated over the next few years in member countries. The main issues which are shaping legislation and hence the use of animals are discussed. They include the need to provide purpose-bred animals whenever possible; the way in which legislation is influenced by the issues of pain; the controls by means of certificates, licenses, inspections, and ethical committees available to government authorities; the need for statistics of use of animals; the impact on toxicity testing; and the likely developments in the future. In conclusion, the way in which scientific advances can alter perceptions of regulatory requirements is exemplified by consideration of acute toxicity testing.

Animal Testing Alternatives↗
PubMed1982

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC working paper 2/6. An appraisal of predictive tests for carcinogenicity.

The history of the development of the DNA damage-induced somatic mutation theory of cancer induction, and of the development of predictive tests for carcinogenicity, is reviewed briefly. On the basis of present information, it is concluded that all predictive tests for carcinogenicity of chemicals should be based primarily on validation using established carcinogens and non-carcinogens. The validation studies reported frequently suffer from limitations in design. Predictive tests pass through three stages during validation. First, the developing tests have been subjected to limited validation but show sufficient promise to warrant further development. 10 such tests are identified from the 100 tests reported in the literature. The second stage test can be considered as developed, when adequate validation studies have been completed to enable the selection of a test for its particular performance criteria. Only 9 such tests were identified of which only 1 still requiring further development can be considered as a useful primary screening test. 2 further tests can be considered as confirmatory tests to be used as a back-up to bacterial mutation assays. Finally, the established tests have been validated on a large scale in several laboratories. At present there is only one established test, namely the Salmonella/microsome test (Ames test). A second assay, based on E. coli, may be considered in this category because of its similarity to the Salmonella test. In conclusion, some guidelines for using predictive tests for regulatory and other purposes are given.

Animals↗
PubMed1981

Chromosomal analysis in vinyl chloride exposed workers: comparison of the standard technique with the sister-chromatid exchange technique.

A group of 21 workers occupationally exposed to vinyl chloride and 6 controls were examined for the presence of chromosomal aberrations or sister-chromatid exchanges in their peripheral lymphocytes. These people comprised a second sampling from a group of exposed workers and controls first examined 18 months earlier. The vinyl chloride exposed workers showed levels of chromosomal aberrations elevated above those of the controls, but there was only a slight increase in sister-chromatid exchanges (per cell or per chromosome) and this increase was not statistically significant. Sister-chromatid exchanges (SCEs) were also examined from in vitro cultures of lymphocytes exposed in G0/early G1 and late G1/early S phase to vinyl chloride, both with and without metabolic activation. There was no increase in SCEs in vitro without metabolic activation but there was a marked increase with metabolic activation and this increase was shown to be independent of cell-cycle phase. It thus was apparent that the small increases of SCEs in workers were not due to the inability of vinyl chloride to induce SCEs in human lymphocytes but were probably because of low exposures and SCE levels could have returned to normal relatively quickly after exposure. The present study suggested that the analysis of longer-living conventional chromosomal aberrations appeared to be a more sensitive monitor of exposure to vinyl chloride in exposed workers than the estimation of SCEs; however, it should be noted that in a 3rd sampling taken 24 months later the exposed workers had chromosomal aberration levels similar to the controls.

Cells, Cultured↗
PubMed1981

Comparison of dominant lethal and heritable translocation methodologies.

Groups of male Alderly Park mice of proven fertility were dosed by gavage for 5 consecutive days per week for 8 weeks or 5 consecutive days only with 100 or 150 mg/kg body weight ethyl methanesulphonate (EMS) or by intraperitoneal injection once a week for 8 weeks or once only with 500 mg/kg shikimic acid. Animals dosed in this manner were compared in the dominant lethal and heritable translocation assays. Animals were mated for 2 consecutive weeks following the 8-week treatment and for 8 consecutive weeks after the 1-week treatment: regimes which were thus non-specific and specific respectively for the stages of spermatogenesis. An additional method of measuring dominant lethality involving counting uterine scars after weaning (Soares (1972) Mutation Res., 16, 425-427) was used and also compared with the conventional method. EMS was clearly confirmed as a mutagen but this was not the case for shikimic acid. For screening purposes the dominant lethal 8-week mating assay was much more efficient in return for the same effort for detecting mutagenic responses than an 8-week mating heritable translocation assay, since the induction of dominant lethal effects paralleled the induction of heritable translocations. 8-week treatment with EMS showed increased dominant lethality but severely reduced fertility and the small numbers of male offspring born made potential heritable effects difficult to assess. The 1-week treatment with EMS produced both dominant lethal and heritable effects. Soares' method can be useful for determining dominant lethal effects in a heritable translocation assay. The "sieving" method of mating to determine partial and total sterility questions the necessity for a negative control in a heritable translocation study.

Animals↗
PubMed1981

Lifetime carcinogenicity study of 1- and 2-naphthylamine in dogs.

Groups of male and female beagle dogs were given daily doses of 400 mg of various mixtures of naphthylamines for up to 109 months. Survivors were killed at 128 months. A variety of pathological conditions was diagnosed, but the only effect related to treatment was the induction of bladder neoplasms. All dogs which received pure 2-naphthylamine developed transitional-cell carcinomas of the bladder within 34 months. Two of 8 dogs receiving 6% 2-naphthylamine in 1-naphthylamine developed early carcinoma and 2/8 dogs receiving 0.5% 2-naphthylamine in 1-naphthylamine developed haemangioma of the bladder. Some of the dogs receiving 1-naphthylamine (total dose 950 g) and the controls had focal cystitis or hyperplasia, but no neoplasia of the bladder. These results confirm the carcinogenicity of 2-naphthylamine to dogs. No carcinogenic effect of 1-naphthylamine was observed, indicating that it is at least 200 times less potent as a carcinogen than 2-naphthylamine. The incidence of bladder cancer in dogs fed mixtures of both naphthylamines explains why previous experimental and epidemiological studies of impure 1-naphthylamine have revealed carcinogenicity.

1-Naphthylamine↗
PubMed1980

International programme for the evaluation of short-term tests for carcinogenicity.

A brief report of the design and initial results from the International Programme for the Evaluation of Short-Term Tests for Carcinogenicity is presented. A total of 42 chemicals, including 14 structurally-related, carcinogen/non-carcinogen pairs were coded and submitted for testing in 35 assays. Several of the assays provided good predictions of carcinogenic potential. The results revealed the advantages and disadvantages of the assays used and provide some indication of the applicability of the tests to screening for carcinogenicity.

Animals↗
PubMed1980

Chromosomal analyses in vinyl chloride exposed workers. Results from analysis 18 and 42 months after an initial sampling.

In a previous study (Purchase et al., Mutation Res., 57 (1978) 325-334) it was reported that 57 workers occupationally exposed to vinyl chloride had an increase in the incidence of chromosomal abnormalities in their lymphocytes by comparison with 24 control workers. Since that time (July 1974) threshold limit values for vinyl chloride and plant exposure levels have been reduced. In the present study, 2 further samples from the same population of workers have been analysed for chromosomal aberrations 18 and 42 months after the initial sampling. At 18 months, 21 VC workers and 6 on-site controls were investigated as were 23 workers and 8 on-site controls at 42 months. In the second sampling there was a tendency to an increase in chromosomal abnormalities of VC-exposed workers except in those people who had changed occupation. By the third sampling, however, there was a decrease by comparison with previous samplings and the levels of abnormalities had returned to values similar to those of the controls. Thus, reduction in exposure to vinyl chloride is accompanied by a reduction in the chromosomal abnormalities to levels indistinguishabe from those of controls.

Adult↗
PubMed1980

Inter-species comparisons of carcinogenicity.

The carcinogenicity of 250 chemicals in 2 species, usually the rat and the mouse, was obtained from the published literature through 3 independent sources. Of the 250 compounds listed, 38% were non-carcinogenic in both rats and mice, and 44% were carcinogenic in both species. A total of 43 compounds had different results in the two species, 21 (8%) being carcinogenic in mice only, 17 (7%) in rats only and 5 (2%) having differing results from other species. A comparison of the major target organs affected by chemicals carcinogenic in both species revealed that 64% of the chemicals studied produced cancer at the same site. This comparison of carcinogenic activity in 2 species suggests that extrapolation from results in a single-animal study to man may be subject to substantial errors.

Animals↗