Possible implications from results of animal studies in human risk estimations for benzene: nonlinear dose-response relationship due to saturation of metabolism

Abstract

Summary. To date, all risk assessment studies on benzene have been based almost exclusively on epiderniological data. Wehave attempted a more integrated and quantitative evaluation of carcinogenic risk for hurnans, trying to utilize, in addition to the epidemiological data, all data available, specifically data on metabolism, genotoxicity, and carcinogenicity in small rodents. An integrated evaluation of the globality of the available data seems to suggest a progressive saturation of metabolic capacity both for man and rodents between 10 and 100 ppm. The most susceptible target cells seem tobe different in humans (predominant induction of myelogenous leukemia) and small rodents (induction of a wide variety of tumors). Nevertheless, both epidemiological and experimental carcinogenicity data tend to indicate a flattening ofthe response for the highest dosages, again suggesting a general Saturation of mechanisms of metabolic activation, extended to different target tissues. From a quantitative point of view, the data suggest a carcinogenic potency at 10 ppm two to three times higher than that computable by a linear extrapolation from data in the 100 ppm range. These observations are in accord with the recent proposal of the European Economic Community of reducing benzene time-weighted average occupationallevels from 10 to 5 ppm.

Results of animal studies suggest a nonlinear dose-response relationship for benzene effects.

“…Ulanova and Avilova (8) have shown that the content of phenol in the urine of rats after a single 4-hr inhalation exposure increases much more slowly than the exposure level for levels of exposure above 100 mg/m 3 ( rv30 ppm), suggesting a progressive saturation of metabolism ahove this concentration. Similarly, Grilli et al (9) have found, using a closed inhalation chamber, that metabolisrn of henzene in the chamber foHowed essentialJy zero-order kinetics above 50 ppm (at equilibrium between rat and chamber), and tirst-order kinetics below 50 to 30 ppm. Zero-order kinetics is equivalent to saturation of metabolism.…”

“…By applying a similar extrapolation to the data of Snyder et al (24), we obtain an averaU tumor incidence of 67/1000 mice over controls (9). It has been estimated by the IARC Warking Group (2) that in humans, 100 ppm of benzene over a 45-year working lifetime would include 140 to 170 cases ofleukemia per 1000 exposed workers.…”

“…Grilli et al (9) have examined the response to benzene in 180 different experiments investigating the genotox· icity of benzene. The main categories of these tests of genotoxicity were DNA darnage and repair, mutations, and chromosomal anomalies, including SCEs.…”

“…Grilli et al (9) have discussed in detail the notion that the ratio of tumor latency to life-span is as a first approximation similar in humans and rodents. Assuming that this is so, from the data of Maltoni et al (fJ6) we can make the extrapolation that 100 ppm, 8 hr/day, 5 days a week, for 2 years, will induce an overall tumor incidence of 11111000 rats over controls.…”

Results of Animal Studies Suggest a Nonlinear Dose-Response Relationship for Benzene Effects

“…Grilli et al (9) have discussed in detail the notion that the ratio of tumor latency to life-span is as a first approximation similar in humans and rodents.…”