Clarification: chemical synergism.

to MTBE. According to the EHP article, several scientists held the hope that the "Maltoni" work would clarify questions about MTBE's carcinogenic potential. Despite the enthusiasm ofsome scientists for Belpoggi's results, the most cursory examination of the paper reveals critical issues that show the data have been grossly overinterpreted. Rather than predicting a health hazard, the data indicate that rats tolerate enormous daily oral doses of MTBE without exhibiting evidence of either tumor or nontumor pathology. Leydig cell tumors in high-dose male rats. According to Belpoggi et al., the administration of MTBE as an olive oil gavage to male rats (1.0 g/kg, 4 days per week) was associated with a significant increase in the incidence of Leydig cell tumors. But examination of the total information in the paper shows that the reported effect cannot be attributed to MTBE. The apparent association was due to a survival differential between control and dosed animals. Male rats administered the highest dose ofMTBE survived longer than the control group. It is well known that Leydig cell tumor incidence is age related. The longer a rat survives, the more likely it is to have Leydig cell tumors. Claiming this survival-related effect to be indicative of a human health hazard strains the bounds of scientific logic. This is particularly true since Leydig cell neoplasms are most likely unique to rats and appear to have no predictive utility for human carcinogenic responses (2). Lymphoma and leukemia (combined) in female rats. Belpoggi et al. reported that MTBE increased the incidence of lymphomas and leukemias (combined) in female rats. Since no mention was made of the incidences of these neoplasms individually, one can only assume that neither was significantly elevated. The scientific validity of combining lymphomas and leukemias for statistical purposes is highly questionable. A National Toxicology Program working committee reviewed scientific guidelines and criteria for the combination of neoplasms during the interpretation of rodent carcinogenesis studies (3). According to that group of experienced pathologists, combining certain tumors for statistical purposes is appropriate and might afford enhanced insights into the biological effects of the test chemical. In other cases, however, combinations are unjustifiable and can lead to overestimates of carcinogenic potential. According to the NTP panel, it is reasonable to combine different types of leukemias and to combine different types of lymphomas. But it is not appropriate to combine leukemias with lymphomas. Treatment-associated increases in the incidence of one or the other of these tumors of diverse cellular origin may be suggestive of an oncogenic effect. But, since the incidence of neither was significantly and independently elevated, the authors' interpretation of this portion of the study represents an overestimation of carcinogenic potential. The science of carcinogenic hazard identification and risk assessment has progressed well beyond the days of simply counting tumors and then making grand leaps to unfounded and insupportable conclusions. As we expand our understanding of chemical carcinogenesis and the predictive validity of our experimental models, we must employ critical and scientific thought processes that incorporate the total knowledge about the chemical. The total of pertinent knowledge about the carcinogenic effects of MTBE in laboratory animals shows that: * The oral administration of up to 1 g/kg of MTBE four days a week produced neither neoplastic nor non-neoplastic changes in male and female rats, * The chronic inhalational administration of grossly toxic concentrations of MTBE produced an increased incidence of hepatocellular adenomas in female (but not male) mice and an increased incidence of renal tubular cell adenomas and carcinomas (combined) in male (but not female) rats, * Neither MTBE nor its metabolite, tertiary butyl alcohol, possess genotoxic potential in either in vitro or in vivo models, * A potential metabolite of MTBE, formaldehyde, possesses equivocal genotoxic potential in mammalian models, but *Even when administered at inhalational doses that are lethal to rats and cytotoxic to mice, MTBE possesses no genotoxic potential in in vivo mammalian models. These scientific facts lead to the conclusions that supramaximal inhalational doses of MTBE cause increased incidences of liver neoplasms in female mice and renal neoplasms in male rats. But since MTBE and its metabolites possess no genotoxic potential, the proliferative changes in response to toxic doses are mediated through nongenotoxic mechanisms that require cytotoxicity to precipitate proliferation. Because of the intense odor (and taste) of MTBE, humans will not tolerate either air or water concentrations sufficient to produce the cytotoxic precursors required to promote cellular proliferation. In short, the carcinogenic hazard associated with MTBE has been identified and defined. The human risk, however, appears to be so small that it is essentially nonexistent.