COMPARISON OF THE MAXIMUM TOLERATED DOSE (MTD) DERMAL RESPONSE IN 3 STRAINS OF MICE FOLLOWING REPEATED EXPOSURE TO ACRYLIC-ACID

The dermal response of three strains of mice (ICR, C3H and B6C3F(1)) e xposed to repeated doses of 0, 1 or 4% acrylic acid was examined over 13 wk. Microscopic and gross changes to the skin were classified as be ing indicative of exceeding the maximum tolerated dose (MTD), reaching the MTD, or tolerating the dose based on proposed MTD guidelines esta blished in US Environmental Protection Agency (EPA) Workshops on derma l carcinogenesis bioassays. A significant number of animals in all thr ee strains with repeated exposure to 4% acrylic acid experienced skin irritation that was classified as having reached or exceeded the MTD c ompared with animals exposed to either 1% acrylic acid or the 0% acryl ic acid acetone control. These results were observed within the first 3 wk of exposure, but there was some accommodation to irritation by 8 wk of exposure. Microscopic findings provided a more sensitive index f or exceeding MTD than gross observations taken only at autopsy, but ge nerally correlated well for MTD if gross observations were taken at re gular intervals during treatment. That is, to set MTD, gross observati ons could be used if taken over the entire course of the exposure, but using microscopic findings was generally a more reliable or sensitive measure. EPA guidelines suggest that it is inappropriate to conduct a dermal bioassay at concentrations that exceed the MTD. Acrylic acid a t 4% in acetone clearly exceeded the MTD based on microscopic or gross observation criteria. At 4%, strain differences were evident by gross observation only, with the ICR strain being less susceptible to irrit ation than C3H or B6C3F(1) strains. These strain differences were not apparent with microscopic examination. Acrylic acid at 1% in acetone, although demonstrating signs of minimal irritation, was fairly well to lerated by all mice in all strains. Thus, acrylic acid at 1% in aceton e, one-quarter of the concentration that was in clear excess of the MT D, would be the appropriate dose concentration for lifetime skin studi es based on MTD criteria.