A MULTIDISCIPLINARY APPROACH TO TOXICOLOGICAL SCREENING .1. SYSTEMIC TOXICITY

The toxicity of 10 chemicals, including pesticides (carbaryl, chlordan e, heptachlor, and triadimefon), solvents (carbon tetrachloride, dichl oromethane, tetrachloroethylene, and trichloroethylene), and industria l chemicals [diethylhexylphthalate (DEHP) and phenol] was examined in the liver, kidneys, spleen, thymus, and adrenals of female F344 rats a fter 1 or 14 d of oral dosing. For each chemical, 4 doses were based o n fractions of the acute LD50, which was estimated using an abbreviate d (up-and-down) method. A multivariate analysis (MANOVA) was conducted for each organ using selected measures of toxicity. A post hoc contra st analysis was also conducted for significant MANOVA results in order to determine effective and ineffective doses. A single dose of heptac hlor resulted in necrotic lymphocytes in the spleen and thymus at dose s greater than or equal to 23 mg/kg. Triadimefon altered liver and spl een weights; this effect has not been described previously. Dichlorome thane (greater than or equal to 337 mg/kg/d for 14 d) increased the in cidence of necrosis of individual centrilobular hepatocytes. Trichloro ethylene-induced hepatotoxicity was obtained at doses an order of magn itude lower than those reported in the literature. Acute DEHP (150 mg/ kg) increased mitotic figures in hepatocytes, which were replaced by h epatocellular cytomegaly after 14 d of dosing at the same level. Follo wing phenol exposure, there was an increased incidence in hepatocellul ar necrosis at 1 d, and an increased incidence of kidney lesions at 1 and 14 d; these findings were considered to be the result of vascular stasis. Overall, the algorithm used to select doses was effective for both 1- or 14-d dosing regimens. For all chemicals except carbon tetra chloride, the lowest effective dose for systemic toxicity was within t he range of 3-56 % of the LD50 for acute dosing, and 1-30 % of the LD5 0 for repeated administration.