Re: Arsenic carcinogenicity testing.

In their letter to EHP, Huff et al. (1) maintained that arsenic is still viewed as "a paradoxical carcinogen; that is, carcinogenic to humans but not to laboratory animals," and that this paradox will be believed until car-cinogenicity of arsenic is demonstrated in animal experiments such as "long-term inhalation studies using arsenic trioxide." Huff et al. (1) seem not to take into consideration , however, that a researcher never has at his disposal an animal population com-mensurable with human populations for which even low carcinogenic risk may be attributed to an exposure, based on epidemi-ologic data, with a sufficient statistical significance. Even under carcinogenic exposure, even most common cancers are still rather rare events. For example, an additional 50 lung cancers per 100,000 workers exposed to arsenic trioxide aerosol in copper smelters would constitute a very high risk level, while probably no cancer would be detected after exposing 100 rats to the same aerosol, provided the risk is the same. To attempt to circumvent this statistical obstacle, we might expose rats to much higher concentrations of M2 0 but under such an exposure, development of a severe intoxication would be highly probable, and rats with a dramatically shortened life span might never survive until the appearance of cancer. The same argument is valid if drinking water is used as the medium for administering arsenic. It seems much wiser to use experimental models, giving opportunity to concentrate a sufficiendy high and long-term exposure on a small part of a target organ only, thus reducing systemic toxicity of the tested chemical to a minimum. Of course, such a model would be difficult to use directly for any standard setting, but it would be adequate for proving that the chemical is carcinogenic (at least for one organ). Twelve years ago we published results of such an experiment (2), which Huff et al. (1) failed to mention in their brief overview. The English version of the summary of our paper (verbatim as translated by the publishers) is as follows: Out of 18 albino rats which survived 17-24 months after implantation in a partially isolated glandular stomach compartment of a perforated polyethylene capsule containing 8 mg arsenic trioxide in a fat wax mixture as vehicle , two developed muconodular adenocarcino-ma and one-mucoid cystic adenocarcinoma in that gastric compartment; metastasis in the liver was detected in one animal. No malignant tumors were found in 9 rats …