Solvents on the skin Kronevi, T., Wahlberg, J. & iolmberg, B. (1979). Histopathology of skin, liver, and kidney after epicutaneous administration of five industrial solvents to guinea pigs. Enuir. Res. 19, 56. Five industrial solvents, n-hexane, toluene. carbon tetrachloride, 2-chloroethanol (ethylene chlorohydrin) and n-butyl acetate, were applied in glass cells containing 1 ml of solvent to 3.1-cm’ areas of the clipped dorsal skin of guinea-pigs for 15 min, or for 1, 4 or 16 hr. Whole-skin samples from the treated areas were then taken for examination. The first four of these solvents caused progressive nuclear pyknosis and separation of the basement membrane from the basal cells. The former effect was apparent within 15 min of application; the latter generally developed somewhat later although it was found in all the samples taken after n-hexane treatment. Pseudoeosinophilic, infiltration appeared in the upper dermis 4 hr after the start of exposure to the first three solvents. Spongiosis (intercellular oedema in the epidermis) was observed 15 min after application of toluene or carbon tetrachloride, but not after other compounds. The fifth solvent (n-butyl acetate) failed to induce any lesion. Carbon tetrachloride caused marked hydropic changes in the hepatocytes of the central areas of the liver lobules and an accompanying loss of glycogen 16 hr after the start of exposure. With 2-chloroethanol, there were centrilobular hydropic changes after 15 min or 1 hr of treatment, again with reductions in glycogen stores; at 16 hr these centrilobular hydropic changes were less pronounced than those seen with carbon tetrachloride, but necrosis was greater. Hexane, toluene and n-bhtyl acetate induced no changes in liver morphology. None of the five solvents altered kidney morphology. Thus among these five solvents, the least watersoluble and more lipophilic compounds, n-hexane and toluene, produced the most severe skin lesions, while systemic effects in the form of liver lesions were a bigger problem with the water-soluble carbon tetrachloride and 2-chloroethanol. The exception, n-butyl acetate, with a solubility in water lying between those of carbon tetrachloride and 2-chloroethanol, showed neither dermal nor systemic toxicity under these experimental conditions. Carcinogenicity
of epoxy resins
Holland, J. M., Gosslee, D. G. & Williams, N. J. (1979). Epidermal carcinogenicity of bis(2,3-epoxycyclopentyl)ether, 2,2- bis(p-glycidyloxyphenyl)propane and m-phenylenediamine in male and female C3H and C57BL/6 mice. Cancer Res. 39, 1718. Epoxy resins are used extensively for protective coatings, in paints and in adhesives. During 40 yr of production they have been found to be allergens (Cited in F.C.7: 1978, 16, 503) but there has been no definitive evidence of carcinogenicity. The uncured resins are bifunctional alkylating epoxides, and some aromatic epoxy resin monomers are known to be mutagenic in strains of Salmonella typhimurium (ibid
Vol. 18. no. 4
1979, 17, 420). Such properties suggest that the uncured resins should be investigated as potential mutagens or carcinogens in higher organisms. Previous skin-painting and injection studies using mice have been inconclusive, but in the paper cited above Holland et al. claim to have demonstrated weak carcinogenic activity in two uncured epoxy resin monomers. The monomers, bis-(2,3-epoxycyclopentyl) ether (I) and 2,2-bis-(p-glycidyloxyphenyl)propane (II), and a polymerizing agent, m-phenylenediamine, were tested for carcinogenic potential on mouse skin. Preliminary investigations, which indicated hepatorenal toxicity by I and m-phenylenediamine, were used to determine suitable dose levels for the carcinogenicity study, the two dose levels given in each case being the maximum tolerated dose and 20% of that level. Each compound was applied 3 times/wk for 2 yr to the shaved dorsal skin of groups of 40 C3Hf/Bd mice of each sex and 20 C57BL/6Bd mice of each sex. Compound I increased epidermal-tumour incidence at the high dose levels in both strains (75 mg/wk in C3Hf/Bd and 37,5mg/wk in C57BL/6Bd mice) but had no such effect at the lower doses. Compound II produced skin tumours only in C57BL/6Bd mice, with a total of eight turnours, including seven carcinomas in the 40 mice given 75 mg/wk but only a single papilloma amongst 40 animals tested with the lower dose. Control mice of this strain did not develop any skin tumours. An equal-parts mixture of I and II exhibited a dramatic synergistic effect on the incidence of skin tumours in both strains. In the more sensitive C57BL/6Bd strain, for example, the 40 mice treated with the mixture of 75 mg/wk included two with papilloma, 24 with localized carcinoma and six with metastatic carcinoma. Individually the high doses of I and II produced four and seven mice, respectively, with localized carcinoma, but none with metastatic carcinoma, and in addition there was one mouSe with a papilloma in each of these groups. The potencies of I, II and the mixture were shown statistically to be low compared with the results obtained with the established skin carcinogen benzo[a]pyrene (BP). Further, gross inspection and autopsy demonstrated that systemic absorption of I and II had not been sufficient to increase tumorigenesis significantly in other body tissues, except in the lungs of C3Hf/Bd mice exposed to the high dose of I. Whilst m-phenylenediamine was extremely toxic to both strains, it did not produce any skin tumours or substantially increase the incidence of other tumours when tested at the maximum tolerated dose (3 mg/wk). This result will be of interest in connection with the debate on the alleged carcinogenicity of hair dyes. The study brought out other interesting observations. The two strains of mice showed a constant ratio of sensitivity to the induction of epidermal turnours. It was suggested that with knowledge of this ratio, the two strains might be used interchangeably in assessing the relative potency of epidermal carcinogens. The synergistic carcinogenesis with the I-II mixture lead to the speculation that I might be a weak initiator and II a tumour promoter. Alternatively, the effect might have been due to enhanced metabolic activation of one or both compounds by the other within
Cosnirr. To.uico/. Vol. 18. no. 4
the target cell. or to an increase in penetration of either or both monomers of the mixture as a result of the differences in their viscosity and volatility.
molytic anaemia. and suggests that an immunological mechanism may be involved. The
Trimellitic anhydride (TMA). the anhydride of 1,2.4-benzenetricarboxylic acid. is used in the manufacture of plasticizers, as a constituent of alkyd resins. and as a curing agent for epoxy resins. It has been found to induce asthma. rhinitis and a late-onset respiratory syndrome with systemic symptoms, as well as an irritative bronchitis. The data now reported suggest the possible involvement of an immunological mechanism in some responses to occupational exposure to this compound. Two youths, both aged I7 yr, were admitted to hospital because of the repeated occurrence of haemoptysis, over a period of 1 wk in one case and 6 wk in the other. Both complained of increasing shortness of breath over a more prolonged period and one also of wheezing and both had haemolytic anaemia. The symptoms were most severe when the patients were at work. Both men worked in a room where cattle pens were first cleaned in a caustic liquid, then sprayed with a powdered mixture of epoxy resin and TMA and finally heated, to enable the resin to liquefy. The powder, which was applied by an air jet and was precipitated on the pens electrostatically, contained 55% TMA, 6&700,;, epoxy resin and about 307; titanium dioxide and other pigments. The procedures were carried out only in ‘semiclosed’ chambers and the standard of ventilation at the time of the mens’ employment appears to have been in some doubt, although at a somewhat later date, after changes had been made, it was described as excellent. A requirement for masks to be worn by those involved with the spraying was not rigidly enforced. In view of their anaemia, both men were treated with iron. They received no other treatment, but they ceased to work at the factory and within a few weeks both the anaemia and other symptoms disappeared. Subsequent examination demonstrated in both men the presence of antibodies against trimellityl human serum albumin and trimellityl human erythrocytes. Consideration of these findings and of the details of several similar cases reported at recent meetings indicates that TMA inhalation may have severe systemic effects, including intra-alveolar haemorrhage and hae-
J. C. (1979). Cyanide, cassava, and diabetes.
Ahmad. D.. Morgan. W. K. C., Patterson, R.. Williams, T. & Zeiss, C. R. (1979). Pulmonary haemorrhage and haemolytic anaemia due to trimellitic anhydride. Lancer II, 328.
Wills, J. H.. Barron, K., Groblewski, G. E., Benitz. K. F. & Johnson, M. K. (1979). Does triphenyl phosphate produce delayed neurotoxic effects? ToxicologJ~ Lett. 4, 21. Whilst it is generally accepted that tri-o-cresyl phosphate is a neurotoxic agent, comparatively little work has been carried out on the neurotoxicity of triphenyl phosphate. A more detailed investigation of this compound’s effect would be desirable, since triphenyl phosphate is a potentially useful component of hydraulic fluids and plasticizers. Whilst it has been shown that triphenyl phosphate (of questionable purity) may be neurotoxic to hens and cats, the pure compound has not been shown to produce this effect in hens and. furthermore, does not appear to inhibit the hen-brain enzyme known as neurotoxic esterase (Johnson. Arch. Tax. 1975, 34, 259). Further work has now confirmed the view that pure triphenyl phosphate does not cause delayed neurotoxic effects. In a limited study using 99.99”/, pure synthetic triphenyl phosphate, five cats were given an SC dose of 0.4. 0.7 or l.Og/kg. The two cats given 0.4 g triphenyl phosphate/kg appeared relatively unaffected by the treatment and were not subjected to autopsy at the end of the experiment. The two higher doses, however, caused prostration a few days after dosing, although histological examination did not reveal any evidence of axon degeneration or demyelination in the spinal cord. These doses of 0.7 and 1.0 g/kg were, in fact, higher than those that had previously been reported to produce such effects in the cat and that apparently also produced neurotoxic effects (Smith et al. Nafn. Inst. HIth Bull. 1932. 160, I). The authors conclude that pure triphenyl phosphate is not neurotoxic and that previous results associating the compound with neurotoxicity were probably due to the presence of impurities in the sample used. There may well be a case. therefore, for using triphenyl phosphate prepared from synthetic phenol instead of the relatively impure triphenyl phosphate which is generally used and which may be obtained from coal-tar sources. [The results indicated much variation between animals, and cannot be considered totally conclusive in view of the small number of animals tested. A repetition of the experiment on a larger scale may well be desirable in order to substantiate the interesting results obtained.]
PRODUCTS Maduagwu, E. N. (1979). Cyanide Toxicology Left. 3, 21. A pdsible
between endemic pancreatic