Biomedical subjects
Rudolph Valentine
Publications and source records attributed to Rudolph Valentine.
Differentiating between local cytotoxicity, mitogenesis, and genotoxicity in carcinogen risk assessments: the case of vinyl acetate.
Understanding the mode of action of carcinogens is critical to scientifically assessing exposure-related risk. Regulatory hazard classification schemes and dose-response assessment paradigms generally require basic knowledge of genotoxic potential to guide decisions on which scheme or paradigm is most appropriate. Although convention suggests that classification and dose-response assessment of genotoxic chemicals should be assessed using conservative assumptions of no threshold, several examples, such as vinyl acetate, exist that challenge this assumption. Vinyl acetate is carcinogenic at portals of entry (nasal cavity and upper gastrointestinal tract). Local metabolism of vinyl acetate produces DNA-reactive acetaldehyde but also produces acetic acid and protons, which contribute to intracellular acidification, cytotoxicity and cell proliferation. This paper reviews their relative contributions to the overall mode of action. Elevated cellular proliferation, well understood to be a risk factor for carcinogenesis, is observed at concentrations associated with tumor formation. Cytotoxicity and compensatory tissue regeneration is one pathway for stimulating cellular proliferation while intracellular acidification is a mitogenic stimulus. Both of these pathways may be operative in nasal tissues while mitogenic proliferation alone appears to be induced in the upper gastrointestinal tract. Using a physiologically-based pharmacokinetic model, quantitative relationships between critical tissue dosimeters and tissue responses are developed to assess the relative importance of genotoxicity and cell proliferation in the overall mode of action of vinyl acetate. This approach supports the concept that intracellular acidification is the sentinel response that precedes cytotoxicity and cellular proliferation. Secondarily, the carcinogenic potential of vinyl acetate is expressed only when tissue exposure to acetaldehyde is high and when cellular proliferation is simultaneously elevated. This mode of action suggests that exposure levels that do not increase intracellular acidification beyond homeostatic bounds will be adequately protective of adverse downstream responses including cancer. These mechanistic insights provide the scientific basis for a cancer classification that incorporates thresholds for cytotoxic and/or mitogenic cell proliferation secondary to intracellular acidification.
Time- and concentration-dependent increases in cell proliferation in rats and mice administered vinyl acetate in drinking water.
Chronic administration of vinyl acetate (VA) in drinking water to rats and mice has produced upper digestive tract neoplasms. These tumors were believed to arise from the intracellular metabolism of VA by carboxylesterases to cytotoxic and genotoxic compounds. We hypothesized that prolonged VA exposure at high concentrations would induce cytotoxicity and a restorative cell proliferation (CP). These endpoints were measured in F-344 rats and BDF1 mice administered drinking water containing 0, 1000, 5000, 10,000, or 24,000 ppm VA for 92 days. On test days, Days 1, 8, 29, and 92, upper digestive tract histopathology and oral cavity CP (pulsed 5-bromodeoxyuridine [BrdU] to measure S-phase DNA synthesis) were evaluated. Analysis of test solutions showed that VA spontaneously hydrolyzed, slowly releasing acetic acid and thereby lowering pH. Statistically significant, concentration-related increases in CP occurred in basal cells of the mandibular oral cavity mucosa of mice at 10,000 and 24,000 ppm but only after 92 days. CP increases were approximately 2.4- and 3.4-fold above controls and were considered to be toxicologically significant. Some statistically significant increases in CP were also measured in the oral cavity mucosa of rats; however, these changes were considered to be of equivocal biological relevance. No histopathological evidence of mucosal injury was seen in either species. The absence of cytotoxicity in the upper digestive tract mucosa suggests that the increased CP at high administered VA concentrations may be due to a mitogenic response, ostensibly from the loss of cell growth controls in oral cavity mucosa.