426 THE CHEMICAL ENVIRONMENT

establish the safety for use in food products of propellants such as octafluorocyclobutane and chloropentafluoroethane, whose gaseous nature at ordinary pressures made feeding experiments difficult to carry out.

In considering the biological activity of the fluoroalkanes, there is a need for further study of the mechanism of their action on the central nervous system and, where appropriate, on the liver. Any relation between the lipophilic properties of halogenated compounds and their biological activity is uncertain, and dehalogenation, which is important in determining the effects of haloalkanes in general, is of minor significance in relation to the fluoroalkanes. It is recommended that mechanism studies should take priority over routine toxicity testing of these compounds if intelligent extrapolations are to be made into the field of public health.

1565. Synergizing chlorofluorohydrocarbon toxicity? Epstein, S. S., Joshi, S., Andrea, J., Clapp, P., Falk, H. & Mantel, N. (1967). Synergistic toxicity and carcinogenicity of 'Freons ' and piperonyl butoxide. Nature, Lond. 214, 526.

The low acute toxicities of the chlorofluorohydrocarbons have been stressed in the previous abstract. We know, however, that synergism cannot be ruled out as a possible factor increasing the acute toxicity of pesticide combinations (Cited ill F.C.T. 1968, 6, 99), and that piperonyl butoxide (PB), which is added to some insecticide formulations as a synergist, has been under some suspicion (so far unsupported by experimental evidence) of acting as a cocarcinogen with certain polycyclic aromatic hydrocarbons (ibid 1965, 3, 857).

The widespread domestic and industrial use of aerosol sprays containing a pesticide, PB and a Freon propellant has raised the possibility of #l vivo interaction between propellant and synergist, with subsequent harmful effects in man. In the present investigation, mice were given subcutaneous injections in tricaprylin of 10 % solutions of Freon 11 (CCI3F; I), Freon 112 (CC12F'CCI/F; II) or Freon 113 (CCI_,F'CC1F2; III), 5 % PB, or combinations of II or III with PB, each in the same concentration as when administered alone. Dosage rates were 0.1 ml on days 1 and 7 after birth and 0.2 ml on days 14 and 21, making a total of 0-6 ml in all. Before weaning at 1 month, the mortality rate was 55 and 46 % in the groups receiving PB combined with II and III respectively, compared with 14% in the controls, 15 % in the animals receiving PB alone and 2-11% in the groups receiving I, II or III alone. Most deaths occurred during the first week of life. After weaning a sex difference appeared, with mortality lower in females than in males, largely because of the development of urinary obstruction in males. Unexpectedly, enhanced to.,dcity in the groups receiving the combined treatments was accompanied from the first week of life by a 10-20 % increase in body weight.

The incidence of liver tumours was highest in the combined-treatment groups and particularly with the combination of II and PB. In these groups, the incidence of hepatoma in male mice over 40 wk old was 24 %, compared with a 4 % overall incidence in the groups receiving one test compound alone. Malignant lymphomas were rare, but were seen in three females given II plus PB.

There is thus no evidence that either PB or the chlorofluorohydrocarbons are carcino- genic. Insufficient data are available to explain the synergistic effect on acute toxicity and apparent hepatocarcinogenicity of combinations of Freons and PB, and the possible relationship between these effects and the increase in body weight remains obscure. The authors suggest that PB may modify a presumed h~ vivo dehalogenation of the Freons.

[This study again underlines the need for further studies on the mechanism of action of the fluoroalkanes and the importance of possible interaction between unrelated compounds likely to be encountered together.]