Study of two cohorts of workers exposed to methyl methacrylate in acrylic sheet production.

OBJECTIVES: To study mortality among 4324 workers at two United Kingdom factories, Darwen, Lancashire and Wilton, Cleveland, producing polymethyl methacrylate (PMMA) sheet. The Darwen factory is still active, but the Wilton one was closed in 1970. Also, to investigate patterns of mortality after exposure to methyl methacrylate; in particular, mortality from colon and rectal cancer. METHODS: All male employees at the Darwen factory with a record of employment in 1949-88 and all men ever employed at the Wilton factory (1949-70) were investigated. The vital status of both cohorts was ascertained on 31 December 1995. The exposure of 1526 subjects at the Darwen plant who were engaged from 1949 onwards could be characterised. The mean duration of exposure was 7.6 years at 13.2 ppm (8 hour time weighted average), although exposures in some work groups were as high as 100 ppm. It was not possible to calculate the cumulative exposure of workers first employed at the Darwen plant before 1949 or workers at the Wilton factory. RESULTS: In the Darwen cohort, 622 deaths were identified and a further 700 deaths in the Wilton cohort. Mortalities for the cohort were compared with national and local rates and expressed as standardised mortality ratios (SMRs). In the subcohort of Darwen workers with more than minimal exposure to MMA, reduced mortalities compared with national and local rates, were found for all causes (SMR 94), and colorectal cancer (SMR 92), but mortality from all cancers was slightly increased (SMR 104). No relations were found with cumulative exposure to MMA. In the subcohort of Wilton workers, mortality from all causes of death was significantly reduced (SMR 89), but mortality from all cancers (SMR 103) and colorectal cancer (SMR 124) were increased. The excess of colorectal cancer was confined to employees with less than 1 year of employment. CONCLUSION: The study provided no clear evidence that employment at the factories or exposure to MMA had adversely affected the mortalities of workers.

Time to discontinue the use of solutions A and B as a cyanide 'antidote'.

Solutions A and B (15.8% ferrous sulfate in 0.3% citric acid and 6% sodium carbonate, respectively) have been available as a first-aid treatment for cyanide ingestion for many decades. Controversy surrounding the efficacy of solutions A and B has existed for much of that time, the main protagonists being in the UK. The current opinion in the UK is that solutions A and B should no longer be used as a first-aid measure in the management of cyanide poisoning. Similarly, oral sodium thiosulfate or activated charcoal should not be used. The recommended first-aid treatment of symptomatic cyanide poisoning is 100% oxygen and amyl nitrite, irrespective of the route of exposure.

Skin irritancy of commercially available alkyl ether sulphate surfactants: is there a difference between those with alkyl chains consisting of even or odd numbers of carbon atoms?

Various concentrations of commercially available alkyl ether sulphate surfactants with alkyl chains consisting of even or odd numbers of carbon atoms have been tested for their primary irritancy to rabbit skin in vivo. All six surfactants (2 with even and 4 with odd carbon number) produced skin irritation. The level of irritation showed dose-dependent increases in the concentration range 4-12% (w/w), with a plateauing of responses of moderate to severe irritation occurring between 12 and 24% (w/w). Recovery generally took 10-14 days to occur. There were no significant differences in the intensity or duration of response between surfactants with alkyl chains consisting of even and odd numbers of carbon atoms.

An in vitro model for identifying skin-corrosive chemicals. I. Initial validation.

An in vitro epidermal slice technique has been developed for identifying chemicals with the potential to cause a corrosive lesion in animal skin in vivo. Skin-corrosive potential has been correlated with the ability to reduce the skin's penetration barrier by lysis of the stratum corneum. This effect was measured as a lowering of the electrical resistance of an epidermal slice following chemical contact in vitro. An initial validation with 68 chemicals showed the technique to have a high sensitivity for corrosive chemicals. The model has potential as a pre-screen for conventional animal tests and, in contrast to in vivo screening methods, has the advantage of providing quantitative and objective data.

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)

An in vitro skin corrosivity test--modifications and validation.

An in vitro rat epidermal slice technique has been developed for identifying chemicals with potential to cause a corrosive lesion in animal skin in vivo. This potential has been correlated with the ability to lyse stratum corneum and has been measured as a lowering of the electrical resistance of the skin slice. Initial validation of the technique with 63 chemicals resulted in a high sensitivity for corrosive chemicals but a lower specificity for irritant chemicals. Subsequent modification relating to chemical contact resulted in an improved specificity (i.e. fewer false positives) at the expense of a small loss in sensitivity (i.e. an increase in the number of false negatives). An intralaboratory double blind trial with 34 corrosive chemicals and 36 irritants showed the technique to have total sensitivity (i.e. no false negatives) and a specificity of 88%. The results of the initial validation and the double blind trial illustrate the robust nature and high reproducibility of this in vitro technique for identifying skin-corrosive chemicals. Overall the model has considerable potential as a pre-screen for conventional animal tests with the additional advantage of providing objective and quantifiable information.

An in vitro epidermal slice technique for identifying chemicals with potential for severe cutaneous effects.

We have developed an in vitro model, using epidermal slices, to identify skin-corrosive potential. Such potential has been correlated with the ability to lyse stratum corneum, indicated by a lowered electrical resistance of the skin slice. Using 41 corrosive and 22 irritant chemicals, a comparison of in vitro and in vivo classifications has shown that this in vitro technique identifies corrosive agents with high precision. Therefore the model has considerable potential as a prescreen to conventional animal tests and, unlike in vivo screening tests, can provide both objective and quantifiable data.