New chloracnegens

A. R. MacKenzie
Director, Discovery Chemistry
S. Brooks
Head of Research Safety & Environmental Group
Pfizer Ltd., U.K.

Chemical & Engineering News (23 Nov 1998) Vol. 76, No. 47.

We wish to alert your readers to a new class of chloracnegen (structures I-IV). These compounds were identified following the diagnosis of chloracne in a small number of our chemists, all of whom had been in the same laboratory, and the majority of whom were involved in the same research project.

Chloracne is a rare skin condition. It is typically caused by workplace exposure—through the skin or by inhalation—to certain halogenated aromatic organic chemicals. The condition involves an increase of keratin in the skin and a reduction in the capacity to produce sebum. This typically leads to the development of acnelike spots or lesions on the face and neck, and sometimes on other parts of the body. Chloracne can take from several months to several years to clear, depending on the level of exposure and the speed with which the causative agent(s) can be expelled from the body [Chem. Brit., 34, 68 (1998)].

Following independent diagnosis of chloracne, we suspended the research project and closed the laboratory. Careful monitoring showed no other cases of chloracne among our broader community of chemists, and a detailed and lengthy investigation was undertaken to identify the causative agent(s). There was no evidence to suggest that known chloracnegens had been inadvertently synthesized, and so, with independent advice, we developed a screening program to identify a potential new class of chloracnegen among the chemicals used in the laboratory.

The results of the screening clearly indicate that novel structures (I-IV) have the potential to be potent human chloracnegens. These structures were all synthetic intermediates in the suspended research project. In our judgment, these structures are representative of a general class of compounds (V), which should also be considered as potential chloracnegens in humans.

The compounds in this structural class have not previously been described as chloracnegenic. However, they exhibit the basic structural features and physicochemical properties that we now understand as typical of known chloracnegens. Thus, they are planar, lipophilic, polycyclic halogenated compounds. In addition, although we have not tested compounds I-IV, a common feature of known chloracnegens is high metabolic stability.

We have commissioned further independent research to better understand the effect of these compounds on human cells. Preliminary findings suggest that the compounds may be less metabolically stable than known chloracnegens, and therefore more rapidly expelled from the body. The visible recovery of our chemists appears to support this possibility.

It is important to recognize that these compounds were handled in very small amounts (milligram to gram scale) and following safety procedures that would be typical of many carefully managed synthetic or medicinal chemistry laboratories. These materials should therefore be regarded as potent chloracnegens, with exposure to a very small amount sufficient to cause chloracne.

Given our experience, we strongly recommend that chemists do not design synthetic routes incorporating these structures. Should work with these compounds be absolutely necessary, appropriate control measures should be employed to prevent exposure by any route.

We are pleased to report that all the affected individuals are recovering well from the condition and none had to take time off work as a result of the condition. Nevertheless, all continue to undergo medical monitoring as a precaution.

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